Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:18]#[N:19].[I:20]CI>>[I:20][C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:18]#[N:19]
Reactant: CC(C)n1ncc(C#N)c1N
Reactant: ICI
Agent: CCCCCON=O
Product: CC(C)n1ncc(C#N)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Amyl nitrite (13.00 g, 111.0 mmol) was added to a suspension of 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (1.77 g, 11.8 mmol) in Diiodomethane (56.0 mL, 695 mmol) at −10° C. in 30 min. The mixture was stirred for 30 min at room temperature and then heated at 100° C. for 2 hours. The mixture was then cooled and concentrated in high vacuum to give a residue which was partitioned between ethyl acetate and 5% Na2S2O5. The organic layer was washed with water, 0.1% of aq HCl, water, brine, dried and concentrated in vacuum. The residue was purified on silica column eluting with 20-30% ethyl acetate in heptane. Yield 1.68 g (55%). MS(ESI+): 262.2
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2/[C:11](=O)[CH2:12][CH2:13][C:14]3[C:19]/2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:24][OH:25].N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:24]\[OH:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(/C=C2/C(=O)CCc3ccccc32)cc1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one (50 mg, 0.16 mmol) and hydroxylamine hydrochloride salt (22 mg, 0.32 mmol) was added into pyridine (2.0 ml) and then stirred overnight at reflux condition. Cooled to room temperature, dichloromethane (40 ml) was added, washed twice using 2 N hydrochloric acid (40 ml) and again washed twice using the saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was made to solid by adding diisopropylether and n-hexane, filtrated and dried. As a result, 36.7 mg of the present compound (productive yield 70%) was obtained as a white solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[C:11]([O:15][C:16]([O:18][C:19]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:23]([CH3:55])[C:22]([OH:56])=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([O:18][C:19]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:23]([CH3:55])[C:22]([O:56][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(OC(=O)c2cccnc2)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Nicotinoyl chloride hydrochloride (2 g) was added under ice-cooling to a mixture of 1-tert-butoxycarbonyloxy-2,3-dimethoxy-4-hydroxy-6-(10-trityloxydecyl)-5-methylbenzene (10 g), triethylamine (2 g) and dichloromethane (30 ml), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water followed by an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate/hexane (1:1) to obtain 1-tert-butoxycarbonyloxy-2,3-dimethoxy-6-(10-trityloxydecyl)-5-methyl-4-nicotinoyloxybenzene (5.1 g). This compound was dissolved in methanol (35 ml). Concentrated hydrochloric acid (2 ml) was added, and the mixture was heated under reflux for 30 minutes. The mixture was concentrated under reduced pressure. Ether was added to the residue which was then separated by filtration to obtain the desired compound (2.9 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.[NH3:28]>CO>[NH2:28][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1
Reactant: N
Reactant: COc1cccc(C(=O)Nc2ccc(OCCBr)c(-c3ccnn3C)c2)c1
Solvent: CO
Product: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 53 %

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide (0.5000 g, 1.161 mmol) and ammonia (0.2515 g, 11.62 mmol) in 20 mL of methanol were heated to 150° C. for 30 minutes under microwave irradiation in a heavy walled sealed tube. The reaction mixture was concentrated to produce the crude product that was subjected to purification on HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid (TFA salt) in 53% yield. LCMS m/z (%)=367 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.83 (dd, J=2.53 and J2=8.89 Hz, 1H), 7.68 (d, J1=2.53 Hz, 1H), 7.53 (d, J1=8.08 Hz, 1H), 7.48 (m, 1H), 7.46 (d, 31=1.78 Hz, 1H), 7.43 (d, J1=8.08 Hz, 1H), 7.19-7.13, (m, 2H), 6.27 (d, J1=1.77 Hz, 1H), 3.95 (t, J1=5.80 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 2.8 (t, J1=5.80 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH:13]1C=CC=CC=1>CCOCC>[CH3:1][O:2][C:3](=[O:11])[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:13]
Reactant: c1ccccc1
Reactant: COC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: C=C(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The compound was synthesized according to a literature method (Ames and Davey J. Chem. Soc. 1958, 1798). To a solution of phenylacetic acid methyl ester (13.58 ml, 100 mmol) in 35 ml of benzene was added diethyl glyoxalate (20.72 ml, 130 mmol). The solution was allowed to stir at room temperature for 1 hour at which point a solid mass was obtained. Suspending the mass in ether followed by filtration yielded a white powder. The white powder was then suspended in ether and acidified using 5% HCl. The aqueous layer was then removed and the ether layer was washed with saturated NaHCO3, H2O, and brine, dried over MgSO4 and then concentrated under reduced pressure. The resulting yellow oil was charged with 45 ml of 37% formaldehyde solution (in water) and 100 ml of water at room temperature. 40 g K2CO3 in 50 ml of water was added via addition funnel to the reaction mixture over a period of 30 minutes. The reaction was then stirred for a further 2 hours at room temperature. The resulting mixture was extracted with ether three times, and the resulting ethereal solution was washed with water, brine, dried over MgSO4, and subjected to Kugelrohr distillation (83° C., 0.5 mmHg) to afford the title compound as an oil (81% yield, 14.1 g). 1H NMR (CDCl3, 300 MHz) δ:7.50-7.30 (m, 5H), 6.35 (d, J=1.2 Hz, 1H), 5.90 (d, J=1.2 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [I-].[K+].[CH2:3]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH3:4].[CH3:12][CH:13]([CH3:16])[CH2:14]O>O.ClCCl>[CH2:3]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH2:12][CH:13]([CH3:16])[CH3:14])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCc1ccc(N)cc1
Reactant: CC(C)CO
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(NCC(C)C)cc1
Temperature: 150 °C
Reaction time: 0.05 h

Procedure:
To potassium iodide (5342 mg, 32.2 mmol), [Cp*IrCl2]2 (128 mg, 0.161 mmol) and 4-ethylaniline (2 mL, 16.09 mmol) at room temperature, was added 2-methylpropan-1-ol (5.94 mL, 64.4 mmol), followed by water (10 mL). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 90 minutes. After cooling the reaction mixture was diluted with water (10 mL) and dichloromethane (20 mL) then stirred vigorously for 3 minutes. The organic phase was separated by hydrophobic frit. The aqueous phase was diluted with further dichloromethane (10 mL) and again stirred vigorously for 2 minutes, then the organics separated by hydrophobic frit. The combined organic fractions were evaporated in vacuo to give the crude product as a brown oil. The crude was purified by silica (Si) chromatography (0-50% dichloromethane-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 2.612 g, as a pale yellow oil. LCMS [LCMS1] Rt 0.96 min, m/z (ES+) 178 (M+H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])(=O)[CH3:2].Cl.[NH2:36][OH:37]>C(O)C.C(OC(C)C)(C)C>[OH:37][N:36]=[C:1]([CH3:2])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34]
Reactant: NO
Reactant: CC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC(CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)=NO
Temperature: 25 °C
Reaction time: 40 h
Yield: 42.3 %

Procedure:
A mixture of (3RS)-1-acetylmethyl-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1, 4-benzodiazepine-2-one (0.42 g), hydroxylamine hydrochloride (62.5 mg) in ethanol (20 ml) was stirred at room temperature for 40 hours. The mixture was evaporated to dryness and the residue was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (40:1). The fractions containing the objective product were combined and evaporated to give a pale green oil, which was pulverized in diisopropyl ether to afford (3RS)-1-(2-hydroxyiminopropyl)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1, 4-benzodiazepine-2-one (177 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1>>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: CN1CCC[C@H]1CO
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Product: CN1CCC[C@H]1COc1nccs1
Yield: 73.8 %

Procedure:
(S)-(-)-1-Methyl-2-pyrrolidine methanol (484 mg, 4.2 mmol) was reacted with NaH ((80% dispersion in mineral oil) 0.164 g 5.46 mmol) and 2-bromothiazole (0.417 g, 4.62 mmol) according to the procedure outlined in Example 3a to afford after column chromatography eluting with (10% MeOH/CHCl3 +1% NH3) (616.2 mg, 3.1 mmol, 74% yield) of 2-(1-methyl-2-(S)-pyrrolidinylmethoxy)-thiazole. The pure base was then converted to its hydrochloride salt by treating the amine (109.4 mg, 0.552 mmol) with a saturated solution of HCl in Et2O dropwise with stirring until no more precipitate formation was observed. This afforded 21.2 mg, 0.09 mmol, 16% of the title compound. mp=99°C. [α]D20 =+2.86° (c=0.021, MeOH). MS (DCI/NH3) m/e 199 (M+H)+. 1H NMR (CD30D, 300 Mz) δ: 7.18 (d, J=4.04 Hz, 1H), 6.99 (d, J=4.04 Hz, 1H), 4.85 (dd, J=12.50, 3.31 Hz, 1H), 4.65 (dd, J=12.5, 6.62 Hz, 1H), 4.09-3.85 (m, 1H), 3.85-3.65 (m, 1H), 3.03 (br s, 3H), 2.45-2.3 (m, 1H), 2.3-1.95 (m, 3H). Analysis calculated for C9H15N2OSClΩ0.6 H2OΩ0.1Et2O: C, 44.63; H, 6.85; N, 11.07; Found: C, 44.68; H, 6.46; N, 10.68.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([CH3:29])[CH:12]=1)#[N:10].O>CN(C=O)C>[Br:8][C:21]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=2[CH3:29])[C:18]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCc1cccn1-c1ccc(C#N)cc1C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(Br)n1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (4.76 g, 1 equiv) was added portionwise to a solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate in DMF at 0° C. during 45 min. After addition, the mixture was stirred at room temperature for 30 min, then poured into water, and extracted with ethyl acetate for three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=15:1) to afford ethyl 3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27](I)=[N:26][N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1[C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:15]3[CH:14]=[C:13]([C:11]([N:8]4[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:37])[CH3:1])[CH2:6][CH2:7]4)=[O:12])[CH:18]=[CH:17][CH:16]=3)[CH:20]=2)[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:26]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CN(C)CCN1CCN(C(=O)c2cccc(-c3cnc4c(c3)c(I)nn4COCC[Si](C)(C)C)c2)CC1
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: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(OC)c1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 120 °C

Procedure:
A mixture of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (50 mg, 0.079 mmol), 2,6-dimethoxyphenylboronic acid (22 mg, 0.118 mmol), tetrakis(triphenylphosphine)palladium(0) (9.1 mg, 0.10 mmol) and sodium carbonate (2M aqueous solution, 0.119 mL, 0.237 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 120° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford (3-(3-(2,6-dimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)(4-(2-(dimethylamino)ethyl)piperazin-1-yl)methanone as a clear oil.
Reaction SMILES: [CH2:1]([Si:19]([CH3:22])([CH3:21])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O.C(Cl)([Cl:30])=O>ClCCCl>[CH2:1]([Si:19]([CH3:22])([CH3:21])[Cl:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC[Si](C)(C)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCCCCC[Si](C)(C)Cl
Yield: 87 %

Procedure:
To the same reactor as used in Example 1 were added 82.2 g (0.25 mole) of octadecyldimethylsilanol, 330 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 75.5 g of octadecyldimethylchlorosilane.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33].C([O:37][B:38](OC(C)C)[O:39]C(C)C)(C)C>C1COCC1>[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:22]([B:38]([OH:39])[OH:37])=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1c(=O)c2cn(COCC[Si](C)(C)C)cc2n(C)c1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (1.26M, 28.4 mL, 35.8 mmol) was added dropwise to a solution of diisopropylamine (3.63 g, 35.8 mmol) in THF (20 mL) at −78° C., keeping the internal temperature below −40° C. Once the addition was complete, the contents of the flask were allowed to warm to −5° C., then were re-cooled to −78° C. The resulting mixture was cannulated over a period of about 30 minutes into a suspension of 1,3-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1) (6.93 g, 22.4 mmol) in THF (75 mL) at −78° C. The mixture was stirred at −78° C. for 30 minutes, then triisopropylborate (8.3 mL, 35.8 mmol) was added dropwise. The solution was stirred at −78° C. for 1.5 hours, then was quenched by carefully adding sat ammonium chloride (200 mL). The mixture was allowed to reach room temperature and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with magnesium sulfate and the solvent was removed under vacuum. The crude material was triturated with ether/hexane and dried under vacuum at 50° C. The solid was recombined with the mother liquor which was reduced under vacuum. The resultant semi-solid material was triturated with iso-hexane and dried under vacuum at 50° C. to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:17]2[CH2:18][C@@H:13]3[CH2:19][C@H:16]2[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: COC(=O)c1cc(Cl)nnc1Cl
Product: COC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)nnc1Cl
Yield: 41 %

Procedure:
Methyl 3,6-dichloropyridazine-4-carboxylate and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were processed as described in Example 2A to provide the title compound (41% yield). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 4.5H), 1.47 (s, 4.5H), 1.90-2.11 (m, 2H), 2.86 (d, J=9.93 Hz, 1H), 3.40-3.62 (m, 2H), 3.72 (d, J=9.90 Hz, 1H), 3.93 (s, 3H), 3.51 (s, 0.5H), 4.63 (s, 0.5H), 5.05-5.15 (m, 1H), 7.49 (s, 1H); MS (DCI/NH3) m/z 368 (M+H)+.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)([O-:5])=[O:4].Br[CH2:12][C:13]([OH:15])=[O:14]>O.CC(C)=O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]([OH:15])=[O:14])[CH:10]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C(O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)Cn1cc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of potassium hydroxide (32.7 g, 0.58 mol) in water (100 mL) was added to a stirred mixture of 4-nitro-1H-pyrazole (30 g, 0.27 mol) in acetone (500 mL) at room temperature. After 30 min, a solution of 2-bromoacetic acid (38.7 g, 0.27 mol) in acetone (100 mL) was added and the reaction was stirred overnight. The solvent was removed in vacuo, the residue was diluted with water then extracted three times with ethyl acetate and the combined organic layer was concentrated in vacuo. The residue was further extracted with dichloromethane and methanol and the combined organic layer was concentrated in vacuo to afford 2-(4-nitro-1H-pyrazol-1-yl)acetic acid (40 g, 88%).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To the solution of kojic acid (28 g) in DMF (200 ml) was added potassium carbonate (32 g), and the mixture was stirred at room temperature for 30 minutes. After benzyl chloride (25 g) was added, the mixture was further stirred for 60 minutes. The solvent was evaporated. The residue was then extracted with ethyl acetate, washed with water and dried. After the solvent was evaporated, the residue was crystallized from ethyl acetate to give 5-benzyloxy-2-hydroxymethyl-4-oxo-4H-pyran (34.6 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[C:30]3[NH:32][CH2:33][C:34]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:29]3=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:32]3[C:30]4[C:29](=[CH:28][CH:27]=[C:26]([N:23]5[CH2:22][CH2:21][O:20][CH2:25][CH2:24]5)[CH:31]=4)[C:34]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:33]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepare according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (75 mg, 0.27 μmol), 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (75 mg, 0.27 mmol) and a 4.0M solution of HCl in 1,4-dioxane (0.014 mL, 0.055 mmol). After purification 1-(7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.91 (1H, d, J=2.3 Hz), 8.73 (1H, dd, J=4.9, 1.8 Hz), 8.01 (1H, dt, J=7.8, 2.2 Hz), 7.76-7.89 (2H, m), 7.48 (1H, dd, J=8.0, 4.9 Hz), 7.27 (1H, dd, J=17.6, 2.7 Hz), 7.14 (1H, d, J=8.2 Hz), 6.36 (1H, dd, J=8.2, 2.3 Hz), 5.61 (1H, d, J=2.3 Hz), 4.00-4.09 (2H, m), 3.91-3.99 (2H, m), 3.70-3.79 (4H, m), 3.50-3.61 (2H, m, J=12.0, 12.0, 2.5, 2.3 Hz), 2.90-3.02 (4H, m), 2.30 (3H, s), 2.10-2.24 (2H, m), 1.89 (1H, dd, J=13.7, 2.3 Hz), 1.75-1.82 (1H, m). Mass Spectrum (ESI) m/e=511 (M+1).