Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.Cl.[OH:26][C:27]1[C:28]([N+]([O-])=O)=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=[O:31]>C1COCC1.O>[OH:26][C:27]1[CH:28]=[C:29]([C:32]([N+:1]([O-:4])=[O:2])=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=[O:31]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1O
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [La+3]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C=O)cc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.5 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (15.2 g, 0.1 mol) obtained in the same manner as in Reference Example 3 was dissolved in THF (150 ml), to which sodium nitrate (8.5 g, 0.1 mol) and lanthanum nitrate hexahydrate (8.7 g, 0.2 mol) were added, and then a mixture of concentrated hydrochloric acid and water at a ratio of 1:1 (70 ml) was added dropwise over a period of 20 minutes. The mixture was stirred for 40 minutes at room temperature, and the separated organic layer was successively washed with water (50 ml), a saturated aqueous solution of sodium hydrogencarbonate (50 ml), and a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure to give a mixture of the title compounds 4a and 4b as pale red crystals (4a:4b=1:1, 13.3 g, yield 67.5%) (Table 2).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CC1CCNCC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-1-carboxylate (0.0645 g, 0.131 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-7-(piperidin-4-ylmethyl)benzofuran-3(2H)-one (0.0395 g, 77%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:26])=[CH:18][C:17]=2[C:27](=[O:38])[NH:28][C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:32])[CH2:30][CH3:31])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:36]([O:35][C:33](=[O:34])[C:29]([NH:28][C:27]([C:17]1[CH:18]=[C:19]([Cl:26])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:38])([CH3:32])[CH2:30][CH3:31])[CH3:37]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 0.16 g of 4-[4-chloro-2-(1-ethoxycarbonyl-1-methyl-propylcarbamoyl)-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester in 8 mL dichloromethane was added 4 mL of TFA at room temperature. This mixture was stirred at room temperature for 1 hour and then concentrated to dryness in vacuo. The residue was treated with 7 M NH3 in MeOH to adjust to pH 9. It was then chromatographed on silica with 7 N NH3 in MeOH/dichloromethane to provide 72 mg 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid [898746-35-5] (500 mg, 3.08 mmol) in MeOH was added a 2M solution of trimethylsilyldiazomethane in Et2O at 0° C., and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to give the title compound. MS (LC/MS): 177 [M+H]+, 375 [2M+H]+; tR (HPLC conditions k): 2.71
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[N:17][C:16]=2[NH:22][NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](O)=O.CC(OC(C)=O)=O>C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:24]([CH3:25])=[N:23][N:22]=3)[N:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2NN)CC1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(6-Chloro-3-hydrazino-pyridazin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (5.33 g; 15.55 mmol) was treated with 20.0 ml AcOH and then with Ac2O (18.80 ml; 198.89 mmol). It was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with half saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over MgSO4 and purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:15]>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: Cc1ccc2[nH]ccc2c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ccn2C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 4-bromo-5-methylindole (3.55 g, 16.9 mmol) (21) in 10 ml of anhydrous DMF is added to a suspension of sodium hydride (1.01 g, 60% in mineral oil, 25.3 mmol, 1.5 eq.) in 10 ml of DMF under nitrogen at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes, and then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0° C. Iodomethane (2.40 g, 18.6 mmol, 1.1 eq.) is added dropwise, the mixture is stirred at 0° C. for 2 hours, and then is warmed to 50° C. and stirred for an additional 2 hours. The reaction mixture is poured into 100 ml of ice-water, extracted with ethyl acetate (30 ml×3), washed with water and brine dried over anhydrous sodium sulfate. The solvent is evaporated and the product (22) is taken to dryness under high vacuum to give 3.75 g of pure compound. 1H NMR (400 MHz, CDCl3) δ 7.17 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.05 (1H, 4, J=3.2 Hz), 650 (1H, dd, J=0.4, 2.8 Hz), 3.77 (3H, 3), 2.51 (3H, s); MS (+VE) m/z 224 (M+).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1>>[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: OCC1CCOCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc(OCC2CCOCC2)nc1
Yield: 60 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 60% yield starting from ethyl 6-chloronicotinate and tetrahydro-2H-pyran-4-ylmethanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.13 (dd, 1 H), 6.89 (d, 1 H), 4.19 (d, 2 H), 3.86 (dd, 2 H), 3.09-3.50 (m, 2 H, obscured by H2O), 1.95-2.10 (m, 1 H), 1.59-1.70 (m, 2 H), 1.25-1.40 (m, 2 H); MS (ESI) m/z 236[M−H+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:11]1([NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:27][CH2:28]3)[N:3]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:5]=2)[CH2:13][CH2:12]1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NC2CC2)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, the 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with the 4-(4-fluoro-phenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at 90° C. to yield 4-cyclopropylamino-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=397.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](OCC)(=[O:17])/[CH:10]=[CH:11]\[C:12]([O:14][CH2:15]C)=[O:13]>C(O)CC>[O:17]=[C:9]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][CH:10]1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)/C=C\C(=O)OCC
Solvent: CCCO
Product: COC(=O)CC1Nc2ccccc2NC1=O

Procedure:
Orthophenylenediamine (10 g, 92.4 mmol) and diethyl maleate (45 g, 646.8 mmol) were refluxed for 75 h in propanol. The solvent was removed using a rotary evaporator and the residue was purified by column chromatography (ethyl acetate/hexane 1:1).
Reaction SMILES: ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@H:35](O)[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Br)(Br)(Br)[Br:51]>CCOC(C)=O>[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@@H:35]([Br:51])[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Br
Temperature: -17 °C

Procedure:
Anhydrous dichloromethane (5.6 L) was charged into a reactor and cooled to −22° C. or below. Triphenylphosphine (205.4 g, 0.783 mol) was added to the cold solvent and the suspension was stirred to form a solution. The lactol (2a, 209.4 g, 0.559 mol) in solid form was added to the cold solution and stirred for 15 mins. Carbon tetrabromide (278.2 g, 0.839 mol) was added portion-wise while maintaining the temperature of the solution between −22° C. to −20° C. under a flow of nitrogen gas (approx. 30 min). After finishing the addition of CBr4, the temperature was slowly raised to −17° C. over 20 mins. The reaction was judged to be >95% complete by TLC (Rfs 0.61 (α), 0.72 (β), 0.36 lactol; 20% EtOAc in hexanes). The reaction solution was immediately transferred to a vessel containing 230 g of flash chromatography grade silica gel (40-63 microns). The stirred mixture was immediately passed through a pad of silica gel (680 g) in a 2.5 L sintered glass Buchner funnel. The filtrate was concentrated under reduced pressure to about 800 mL and the ratio of α/β isomers of the crude product was 10:1 as determined by 1H-NMR. (CDCl3) δ=6.35, (s, αC1-H), 6.43, (d, βC1-H). The residue was purified by plug column chromatography using 2.1 kg of silica gel in a 6 L sintered glass Buchner funnel and eluted (via suction) with a stepwise gradient elution of 1%, 5%, 8% 12% EtOAc in hexane (ca 4 L each) to remove non-polar impurities followed by 12%, 25% EtOAc in hexane (6 L total) to elute the product. The product containing fractions were combined into two fractions, concentrated under reduced pressure, dried under vacuum (0.1 mmHg, ambient temp., 20 h) to colorless oils. Main fraction (197 g, 89% α/β=20:1). The alpha isomer crystallized from a small portion of the oil upon standing at 0° C. for several weeks to give large, thin plates, mp 59-61° C. The pure beta isomer crystallized from a mixture of alpha and beta product oil from an earlier less selective run to give needles, mp 77-79° C.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH:10]=[O:11])=[CH:5]2.C1(C(N)C2CCCCC2)CCCCC1.Cl[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].CCOC(C)=O>C1COCC1>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([CH:10]=[O:11])=[CH:5]2)=[N:1]1
Reactant: O=Cc1ccc2n[nH]cc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc2cc(C=O)ccc2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2H-Indazole-5-carbaldehyde (Stage 150.5, 770 mg, 5.27 mmol) was dissolved in THF (54 mL) and dicyclohexylmethylamine (1.37 mL, 6.32 mmol) was added. After dropwise addition of (2-chloromethoxy-ethyl)-trimethyl-silane (1.21 mL, 6.32 mmol), the RM was stirred for 48 h at rt. It was then taken into EtOAc and washed successively with 0.5 M aqueous NaOH solution and brine. The organic layer was dried on Na2SO4 and evaporated and the residue purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=100:0->70:30) to afford white crystals of the title compound (tR 7.14 min (conditions 3), MH+=277).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7])[CH3:2].CCN(C(C)C)C(C)C.[NH2:37][NH2:38]>CCO>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8]2[C:5]=1[C:6]([NH2:7])=[N:37][NH:38]2)[CH3:2]
Reactant: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc(F)c1C#N
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc2[nH]nc(N)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
In a microwave tube, 2-(ethyloxy)-4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-6-fluorobenzonitrile (137 mg, 0.371 mmol), 5 mL of EtOH, Hunig's base (0.065 mL, 0.371 mmol), and hydrazine anhydrous (0.070 mL, 2.225 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), and dried under reduced pressure to afford the title compound (120 mg) as a white solid. LC-MS (ES) m/z=382 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, J=7.3 Hz, 3H), 1.35 (m, 1H), 1.44 (t, J=7.0 Hz, 3H), 1.80 (m, 2H), 1.93 (m, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.39 (m, 1H), 3.40-3.45 (m, 1H), 3.48-3.62 (m, 1H), 4.05 (m, 1H), 4.13-4.25 (q, J=7.0 Hz, 2H), 4.99 (s, 2H), 6.17 (s, 1H), 6.40 (s, 1H), 6.92 (s, 1H), 7.44 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:25](O)=[O:26])[C:5]2=[N:6][CH:7]=1.CN1C(=O)CCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:59]([CH2:61][NH2:62])[OH:60].C(N(CC)CC)C>>[OH:60][CH2:59][CH2:61][NH:62][C:25]([C:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:10]([CH2:11][C:12]2[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])[CH:15]=[CH:14][N:13]=2)[CH:9]=1)=[O:26]
Reactant: NCCO
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cnc2c(C(=O)NCCO)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.4 %

Procedure:
See FIG. 23(b). 6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (55 mg, 0.14 mmol) and NMP (13.95 μl, 0.14 mmol) was taken in a 50 ml single necked flask equipped with an air condenser connected to nitrogen source. HATU (66.2 mg, 0.17 mmol) was added to get a suspension. Added ethanol amine (17.50 μl, 0.29 mmol) followed by the addition of triethyl amine (60.6 μl, 0.43 mmol). The reaction mass was stirred at RT for 5 minutes. LCMS showed completion of the reaction. The crude compound was purified by Gilson Prep HPLC to get pure N-(2-hydroxyethyl)-6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (15.00 mg, 24.49%). ES+MS m/z: 423 (M+I). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H ) 2.39 (s, 3 H ) 3.45 (br. s., 2 H ) 3.53 (br. s., 2 H ) 4.83 (s, 1 H ) 4.90 (d, J=9.04 Hz, 2 H ) 5.62 (s, 2 H ) 7.06 (d, J=5.65 Hz, 1 H ) 7.75 (s, 1 H ) 8.07 (s, 1 H ) 8.17 (d, J=5.09 Hz, 1 H ) 8.32 (s, 1H ) 8.79 (s, 1 H ).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].[C:21]1([O:27][C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>>[O:27]([C:28]1[CH:29]=[CH:30][C:31]([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]2[C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=[C:11]([NH2:20])[C:10]=3[N:9]=[CH:8]2)=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Reactant: Ic1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ccccc2c2c1ncn2CCOCC#Cc1ccc(Oc2ccccc2)cc1
Yield: 2.9 %

Procedure:
Using the general method of Example 7, 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.88 mmol) was reacted with 4-iodophenyl phenyl ether (0.78 g, 2.63 mmol). The crude product was purified by column chromatography eluting with 95/5 dichloromethane/methanol to provide a solid. The solid was slurried with aqueous sodium hydroxide to remove salts and then purified by column chromatography eluting with 9/1 ethyl acetate/methanol to provide a solid. This material was further purified by column chromatography eluting with 99/1 ethyl acetate/methanol to provide 24 mg of 1-(2-{[3-(4-phenoxyphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 146-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2CO1
Reactant: OO
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc2CO1

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)[C@H](CNC(=O)c2ccc(Cl)s2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Intermediate 88 (13.4 g, 38.42 mmol) was dissolved in 200 ml DCM and N-methyl piperazine (8.52 ml, 76.83 mmol) was added followed by DIPEA (26.77 ml, 153.67 mmol) and TBTU (18.5 g, 57.63 mmol). After 16 h stirring at RT, the solution was evaporated to dryness and purified by silica gel chromatography. Yield: 13.05 g, 79%.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH2:16])(=[O:4])[CH3:3].[C:17]([O:20][CH2:21][C:22](O)=[O:23])(=[O:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O1CCOCC1>[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH:16][C:22](=[O:23])[CH2:21][O:20][C:17](=[O:19])[CH3:18])(=[O:4])[CH3:3]
Reactant: CC(=O)OCC(=O)O
Reactant: COC(=O)c1ccc(NC(C)=O)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)=O)c(NC(=O)COC(C)=O)c1
Temperature: 0 °C
Yield: 678.9 %

Procedure:
Compound 16 (0.20 g, 0.96 mmol) was dissolved in a mixture of anhydrous DMF (2 mL) and anhydrous dioxane (5 mL), and the solution was cooled to 0°-5° C. in an ice bath. To this were added acetoxy acetic acid (0.124 g, 0.129 mmol) and DCC (0.198 g, 0.210 mL, 0.960 mmol). The reaction mixture was stirred for a few minutes at 0° C., the ice bath was removed, and the mixture was stirred at room temperature for 4 hours. The solid which separated was filtered and the filtrate was concentrated to dryness on a rotary evaporator. The solid residue was triturated with 5% HCl, filtered, and washed on the filter with water. The collected solid was then triturated with 5% NaHCO3, filtered, washed with water, and dried under vacuum to give 17 (270 mg, 70.9% yield) as a white solid: mp 182°-186° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][N:18]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 6-(4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (15 g), 3,4-dihydro-2H-pyran (24 mL) and p-toluenesulfonic acid monohydrate (3.0 g) in THF (400 mL) was stirred at r.t. until the reaction was complete. Water was added and the mixture was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed over a short path column (heptane/ethyl acetate gradient). The product containing fractions were combined, concentrated, and the resulting residue was triturated with ether to give 11 g (57%) of the title compound.