Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][C:13](=C)[CH2:14][O:15][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>C(#N)C.O.C(Cl)(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][C:13](=[O:18])[CH2:14][O:15][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1COc2cc3c(cc2OC1)C(C)CC3
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1CCc2cc3c(cc21)OCC(=O)CO3
Temperature: 30 °C
Yield: 49.6 %

Procedure:
6.6 g (30.5 mmol) of 1-methyl-7-methylene-2,3,7,8-tetrahydro-1H,6H-5,9-dioxacyclohepta[f]indene were dissolved in a mixture of 140 ml of acetonitrile, 140 ml of water and 90 ml of carbon tetrachloride. 6.50 g (30.5 mmol) of sodium periodate were added at room temperature with stirring, with the temperature falling to 15° C. After stirring for 30 min, 0.3 g (1.5 mmol, 5 mol %) of ruthenium (III) chloride hydrate were then added, with the temperature increasing back to 30° C. The mixture was stirred for 48 h at room temperature, in the course of which, after 6 h, a further 6.50 g (30.5 mmol) of sodium periodate and 0.3 g (1.5 mmol, 5 mol %) of ruthenium (III) chloride hydrate were added. The reaction mixture was then poured into 500 ml of water and the product was extracted three times, each time with 200 ml of dichloromethane. The combined organic extracts were washed with 200 ml of 20% sodium hydrogen sulfite solution and 200 ml of water and dried over sodium sulfate. After removing the solvent on a rotary evaporator and flash chromatography (pentane/ether, 4:1, Rf=0.32) on silica gel, 3.3 g (50%) of 1-methyl-2,3-dihydro-1H-5,9-dioxacyclohepta[f]inden-7-one (2) were obtained as colorless crystals of m.p. 79-80° C.
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[N:24]([CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:23]3(=[O:35])=[O:34])=[C:18]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:17]=2)[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.[CH2:56]([NH2:61])[CH2:57][CH2:58][CH2:59][CH3:60]>C(Cl)Cl>[C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[N:24]([CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[S:23]3(=[O:35])=[O:34])=[C:18]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:17]=2)[C:12]([NH:61][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S1(=O)=O
Reactant: CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of (S)-2-benzenesulfonylamino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (70 mg, 0.108 mmol) in methylene chloride (3 mL) is added EDCl (31 mg, 0.162 mmol) and the solution is stirred at RT for 3 min. To this is added n-pentylamine (10 mg, 0.119 mmol) and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound: (M−1)−=713.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13](O)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1.[CH3:28][C:29]1([CH3:37])[O:36][C:34](=[O:35])[CH2:33][C:31](=[O:32])[O:30]1>ClCCl>[CH3:28][C:29]1([CH3:37])[O:36][C:34](=[O:35])[CH:33]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:31](=[O:32])[O:30]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (71.7 g, 0.442 mol) was added portionwise to a stirred solution of heptanoic acid (0.402 mol) in 300 mL of dry dichloromethane. The resulting mixture was stirred at room temperature for 2 hours. A solution of pyridine (35.8 mL, 0.442 mol) and Meldrum's acid (63.7 g, 0.442 mol) in 150 mL of dry dichloromethane were added over a period of 2 hours to the reaction mixture. The reaction mixture was stirred for 16 hours, quenched with 400 mL of 2 N HCl (bubbling), separated, washed sequentially with 2×400 mL 2 N HCl, brine (400 mL), dried (MgSO4), and the solvent was removed in vacuo to give the title compound as aviscous oil. The crude product was used in the next step after spectral characterization.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].C(O)(C)C>C1COCC1>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: BrCCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C1CCCCC1(CCCCCOc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 5 phenoxy pentyl bromide (122.0 g, 0.5 mol) and 2-phenylcyclohexanone (104.4 g, 0.6 mol) in 1.5 L THF, NaH (0.55 mol, 24.0 g) was added portionwise, keeping the temperature between 25° to 30° C. After most of the H2 evolution had ceased, the reaction mixture was heated to reflux for 16 hours under a N2 atmosphere. After cooling to room temperature, 50 mL isopropanol was added and the mixture was concentrated in vacuo to half its volume. This residue was diluted with 2 L ether and 1 L H2O. The layers were separated and the aqueous layer was washed one time with 500 mL ether. The combined organic layers were washed two times each with 500 mL H2O, dried (MgSO4), and concentrated in vacuo to give a solid. Recrystallization from petroleum ether yielded 27.5 g (16.4%), mp 69°-72° C., of the desired product.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Br[CH2:6][CH2:7][CH2:8][C:9]#[N:10]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH:8]([CH2:7][CH3:6])[C:9]#[N:10]
Reactant: N#CCCCBr
Reactant: NCCO
Solvent: CCO
Product: CCC(C#N)NCCO

Procedure:
Dissolve ethanolamine (11.3 g, 0.185 mol) and 4-bromobutyronitrile (32.6 g, 0.22 mol) in ethanol (700 mL) and heat at reflux for 18 hours. Evaporate the solvent in vacuo and purify by distillation to give the title compound.
Reaction SMILES: S(Cl)(Cl)=[O:2].[CH2:5]([O:8][C:9]([N:11]1[C@H:15]([CH:16](O)[C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[CH:19][N:18]=2)[C:14](C)(C)[C@@H:13](C(C)(C)C)[CH:12]1O[SiH3])=[O:10])[CH:6]=[CH2:7].ClCCl>CN(C=O)C.C(O)(=O)C.[Zn]>[CH2:5]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[CH:19][N:18]=2)[CH2:14][C@@H:13]([OH:2])[CH2:12]1)=[O:10])[CH:6]=[CH2:7]
Reactant: O=S(Cl)Cl
Reactant: C=CCOC(=O)N1C(O[SiH3])[C@H](C(C)(C)C)C(C)(C)[C@H]1C(O)c1ncc2sccn12
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ncc2sccn12
Reaction time: 0.33 h

Procedure:
Thionyl chloride (0.39 ml) is added to a solution of 774 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethyl-silyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidine (stereoisomer A) in 0.014 ml of dry DMF and 5.3 ml of dry dichloromethane under ice cooling, and the mixture is stirred in this state for 25 min. The solvent and the excess reagent are removed by evaporation under reduced pressure, and the residue is dried under reduced pressure by means of a vacuum pump to give a bright yellow amorphous material which is then dissolved in 17.7 ml of 90% acetic acid. Zinc (1.156 g) is added to the solution under ice cooling, and the mixture is stirred in this state for 20 min. Further, the ice bath is removed, and stirring is continued for additional 10 min. Distilled water and ethyl acetate are added, and the mixture adjusted to pH 6 under stirring by addition of sodium hydrogencarbonate. The organic layer is separated, and the residual aqueous layer is adjusted to pH 8 by addition of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The combined organic layers are washed twice with an 5% aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and potassium carbonate and filtered. The solvent is removed by evaporation under reduced pressure. The residue, together with acetonitrile, is once subjected to azeotropic evaporation, the residue is redissolved in 17.7 ml of acetonitrile, 0.70 ml of concentrated hydrochloric acid is added thereto under ice cooling, and the mixture is stirred in this state for 15 min. The mixture is diluted with 200 ml of ethyl acetate, the diluted solution is washed with 50 ml of a 5% aqueous sodium hydrogencarbonate solution, the organic layer is dried over magnesium sulfate, filtered, and the solvent is removed by evaporation under reduced pressure to give a yellowish orange amorphous material. The amorphous material is successively purified by column chromatography on silica gel (first, ethyl acetate:methanol=9:1; second, chloroform:methanol 9:1) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 138 mg of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-5-yl)methylpyrrolidine as a colorless amorphous material.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.C(O)(=[O:16])C.C(C(C)=O)C(C)C>O.[Cl-].[Na+]>[O:16]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: CC(=O)NC1CCCc2sccc21
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(=O)NC1CCC(=O)c2sccc21
Reaction time: 0.42 h

Procedure:
A mixture of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-acetamide (2.0 g; 10.25 m mole), cobaltous acetate (0.49 g; 2.77 m mole), cobaltous bromide tetrahydrate (0.635 g; 2.18 m mole), water (0.4 ml), acetic acid (5.0 ml) and methyl isobutyl ketone (35.0 ml) in suitable flask fitted with a reflux condenser, a gas dispersion tube and a thermometer is stirred vigorously. Air is introduced through the dispersion tube into the turbid blue solution at room temperature for 45 minutes, and then the mixture is heated. After 25 minutes, the solution turns greenish blue (temperature: 45° C.) and in 15 minutes green (temperature: 55° C.). The reaction is run overnight with periodic additions of methyl isobutyl ketone. The greyish green reaction mixture containing some suspended dark gray solid is then diluted with water (40.0 ml) and saturated with sodium chloride. The upper organic phase is separated and the aqueous phase extracted with chloroform (2×100 ml). The organic phase and the chloroform extracts are combined, washed with brine (50 ml) and water (25 ml), respectively. The water wash is counter-extracted with chloroform (50 ml) and the chloroform extract added to the above organic phase. The combined organic phase is evaporated in vacuo to afford a gum, which contains the desired compound. The latter is hydrolyzed without further purification and the resultant amine hydrochloride is converted to 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:37][CH2:38][C:39]1[C:40]([OH:47])=[N:41][C:42]([CH3:46])=[CH:43][C:44]=1[CH3:45]>ClCCl.C(N(CC)CC)C>[OH:47][C:40]1[C:39]([CH2:38][NH:37][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])=[CH:14][CH:13]=2)=[C:44]([CH3:45])[CH:43]=[C:42]([CH3:46])[N:41]=1
Reactant: CCCC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 4-(pentan-2-yl)benzoic acid (192 mg, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol), 1-hydroxybenzotriazole t (202 mg, 1.5 mmol), triethylamine (0.5 mL) and dichloromethane (15.0 mL) was stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added to the above mixture. The mixture was stirred at 25° C. for 12 hours. The mixture was washed with water (20 ml×2). The organic phase was dried by sodium sulphate. The mixture was filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methane=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(pentan-2-yl)benzamide as a white solid (100 mg, 40%). LRMS (M+H+) m/z: 326.2. found 326. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.26 (t, J=4.5 Hz, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.23 (m, J=8.1 Hz, 2H), 5.85 (s, 1H), 4.29 (d, J=4.5 Hz, 2H), 2.76-2.69 (m, 1H), 2.17 (s, 3H), 2.11 (s, 3H), 1.54-1.47 (m, 2H), 1.18-1.05 (m, 5H), 0.81 (t, J=14.4 Hz, 3H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[O:19])=[CH:13][CH:12]=1>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:18](=[O:19])[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1

Procedure:
1-(4-Methoxyphenyl)-2-(4-methoxyphenyl)ethanone was prepared from anisole and 4-methoxyphenylacetyl chloride (prepared by heating the commercially available carboxylic acid in thionyl chloride and subsequent concentration) using the method described in step A of Example 9. After step A, the product was chromatographed on silica gel using 3:2 hexane/EtOAc as eluant. 1-(4-methoxyphenyl)-2-(4-methoxyphenyl)ethanone was converted to the title compound following the procedures described in steps C-E of Example 1, except for the following modifications: 1) in step C, the acidic hydrolysis reaction, after dilution with H2O, was extracted 2× with Et2O prior to basification, extraction 3× with EtOAc and isolation of the desired amine after concentration; and 2) the prep HPLC purification of step D utilized 65% solvent B as eluant.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH:10]([C:16]([OH:18])=[O:17])[CH2:9]2>>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH:10]([C:16]([O:18][CH2:1][CH3:2])=[O:17])[CH2:9]2
Reactant: O=C(O)C1Cc2cc(O)ccc2CN1
Reactant: CC(=O)Cl
Product: CCOC(=O)C1Cc2cc(O)ccc2CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 140.4 %

Procedure:
Acetyl chloride (30 mL, 33 g, 422 mmol) was added carefully to ice-cold anhydrous EtOH and the resulting solution was stirred at RT for 10 min. 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3.30 g, 14 mmol) was added and the mixture was stirred at 50° C. for 5 h. The solvent was evaporated and the residue was dried under vacuum to yield ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (4.35 g, crude yield>100%) as a yellow solid. MS expected 222.1 found 222.0. 1H NMR (400 MHz, CD3OD): δ 7.06 (d, J=8.4 Hz, 1H), 6.74 (dd, J=8.0, and 2.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 4.44-4.29 (m, 5H), 3.35 (dd, J=17.2, and 5.2 Hz, 1H), 3.15 (dd, J=17.2, and 11.6 Hz, 1H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[C:9](Cl)[C:8]=1[N+:18]([O-:20])=[O:19])[CH2:4][CH3:5].[NH3:21]>C(COC)OC>[CH3:1][CH2:2][CH:3]([NH:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([NH2:21])[C:10]([CH3:16])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:4][CH3:5]
Reactant: N
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]
Solvent: COCCOC
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]
Temperature: 94 °C

Procedure:
A mixture of 5.00 g. (0.0165 mole) of N-(3-pentyl)-3-chloro-2,6-dinitro-4-methylaniline and 30 ml. of dimethoxyethane was charged to a glass reaction tube. The tube was cooled, 5 ml. of anhydrous ammonia condensed into it, and the tube was then sealed. After heating for 5 hours at 94°C., the tube was opened and the reaction mixture was stripped of volatile material. The residue was taken up in 250 ml. of hot cyclohexane, the solution filtered while hot, then stripped to give an orange residue which was crystallized from 95% ethanol to give 1.02 g. of the desired product as orange needles, m.p. 157°-160.5°C. After recrystallization from 95% ethanol the product melts at 160°-161.5°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(C)Nn1c(CO)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)Nn1c(CO)nc2c(N)nc3c(c21)CCCC3
Reaction time: 18 h

Procedure:
A mixture of [4-amino-1-(isopropylamino)-1H-imidazo[4,5-c]quinolin-2-yl]methanol (0.120 g, 0.442 mmol) and platinum (IV) oxide (0.100 g, 0.422 mmol) in trifloroacetic acid (10 mL) was hydrogenated on a Parr apparatus at 50 psi (3.4×105 Pa) at room temperature for 18 hours. The mixture was diluted with chloroform (20 mL) and filtered through a pad of CELITE filter agent. The filter agent was rinsed with a 4:1 chloroform/methanol solution. The filtrate was concentrated under reduced pressure to yield an oil that was suspended in water (10 mL) and treated with 10% aqueous sodium hydroxide until pH 7 was reached. A white precipitate was isolated by filtration, rinsed with water, and dried overnight under vacuum to provide [4-amino-1-(isopropylamino)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methanol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (11.6 g, 0.05 mol), DMSO (20 ml) and phenethylamine (12.1 g, 0.1 mol) was heated at 80° C. overnight. The reaction mixture was poured into water (1 L) and the precipitate which formed was collected by filtration and washed with water. The solid was dissolved in hot ethyl acetate, and then the solution was dried over MgSO4, filtered and evaporated to a small volume. Hexane was added and then the mixture was cooled in an ice-bath and then the product which crystallized was collected by filtration, washed with hexane and dried to afford 12.5 g of 1-ethyl-N-(phenylethyl)-1H-pyrazolo[3,4-b]quinoline-4 amine, m.p. 157-158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][C@@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@H:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:18])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[Cl:17])[CH:3]=2)[CH2:28][C@@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Reactant: C[C@H]1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Yield: 46.1 %

Procedure:
Dissolve N-(3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1, 200 mg, 0.756 mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Add acetic acid (52 μL, 0.907 mmol) and sodium triacetoxyborohydride (192 mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat the reaction to 45° C. for 4 hr. Cool the reaction to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (20%-75% ethyl acetate/hexane) to yield 161 mg (46%) of the title compound. Mass spectrum (ion spray): m/z 462.4 (M+1); 1H NMR: δ (CDCl3, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.20 (m, 1H), 3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 1.27, (m, 4H).
Reaction SMILES: [CH3:1][P:2]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C([N-]C(C)C)(C)C.[Li+].[C:25]1([CH2:31]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C>O1CCCC1.CCOCC>[C:6]1([CH2:5][O:4][P:2]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH2:1][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CP(C)(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)CP(=O)(CCc1ccccc1)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of [methyl(phenylmethoxy)phosphinyl]acetic acid, methyl ester (1.0 gm., 0.004 mole) in 20 ml. of tetrahydrofuran is added over 50 minutes to a solution of lithium diisopropylamide (0.008 mol.) in tetrahydrofuran maintained at -78° under argon. Following the addition, stirring is continued at -78° for 20 minutes. Phenylmethyl bromide (0.684 gm., 0.004 mol.) in tetrahydrofuran (5 ml.) is then added and the mixture is stirred for 2 hours at -78° and for one hour at 0°. The mixture is then neutralized to pH5 with acetic acid and poured into ether. The ether layer is washed with water, 5% potassium bisulfate and brine, and dried over magnesium sulfate. Evaporation in vacuo yields a residue which is chromatographed on silica gel with dichloromethane/ethyl acetate. The product, [(2-phenylethyl)(phenylmethoxy)phosphinyl] acetic acid, methyl ester (0.66 gm., 50%) is identical by TLC and NMR to that prepared in Example 6.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[N:17][C:18](Cl)=[N:19][CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[Br:14][C:15]1[CH:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 150 °C
Yield: 96.3 %

Procedure:
In a microwave vial were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (110 mg, 0.589 mmol, available from Fluke), 5-bromo-2-chloropyrimidine (95 mg, 0.491 mmol, available from Lancaster) and DIPEA (0.112 mL, 0.638 mmol) in tert-butanol (2 mL). The reaction was stirred and heated in an Emrys Optimizer microwave at 150° C. for 0.5 hr. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated to yield the desired product (162.3 mg)