Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:12])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]#[C:4][CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]([OH:12])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])/[CH:3]=[CH:4]/[CH3:5]
Reactant: CC#CC(C)(O)CCC=C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C/C(C)(O)CCC=C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
A solution of 4,8-dimethyl-7-nonen-2-yn-4-ol (7.78 g; 44.5 mmol) in dry THF (300 ml) was cooled into an ice-water bath, with stirring under nitrogen. Solid LiAlH4 (2.15 g; 53.8 mmol) was added all at once. After 5 minutes, the cooling bath is removed and the reaction is stirred for one hour, then refluxed for 4 hours. After cooling into an ice-water bath, the reaction was treated cautiously with water (2.2 mml), 5% aq. NaOH (6.6 ml) and water (2.2 ml). The reaction was warmed up to room temperature and stirred until a white slurry was observed. Solid anhydrous sodium sulfate (ca 20 g) was added to the mixture in order to dry the medium. The solid was filtered off, thoroughly rinsed with diethyl ether. The filtrate was concentrated in vacuo. The product was purified by column chromatography on silica gel (eluting with heptanes/ethyl acetate 3:1) followed by bulb-to-bulb distillation (75° C./1.2 mbar). The product was obtained as a liquid (3.8 g; 94% pure by GC; 21.3 mmol; yield: 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:27]2[CH2:29][CH2:28]2)([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(#N)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:27]2[CH2:29][CH2:28]2)([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CSC)cccc12)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 62 mg (0.15 mmol) of the compound from Example 105A in 0.5 ml of tetrahydrofuran was added dropwise to 0.51 ml (0.51 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 1 ml of tetrahydrofuran at RT under argon. The mixture was stirred at 60° C. for 1 h and then mixed with water and acetonitrile, and the suspension was filtered through kieselguhr. The solvents were removed in a rotary evaporator, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 52 mg (93% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[OH:11].[CH3:12][N:13]1C(=O)O[C:16](=[O:17])[C:15]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:14]12>>[CH3:12][NH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([OH:11])=[N:6]1)=[O:17]
Reactant: Oc1n[nH]c2ccc(Cl)cc12
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Product: CNc1ccccc1C(=O)n1nc(O)c2cc(Cl)ccc21
Yield: 32.3 %

Procedure:
5-Chloro-1H-indazol-3-ol was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 32.3% yield; m.p. 206°-208° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:27])([CH3:26])[CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:27])([CH3:26])[CH2:23][CH2:24][O:25][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)(CCO)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
4-[4-(2,4-Dihydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (3.75 g, 9.9 mmol), tosyl chloride (2.07 g, 10.8 mmol), dichloromethane (38 ml) and triethylamine (2.75 ml, 19.7 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.16 ml, 1.0 mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→40:60) to afford the title compound as a colorless oil (4.69 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O1CCOCC1.[OH-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCOc1ncc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A solution of 5-bromo-2-ethoxypyridin-3-amine (53 mg, 0.25 mmol) and diisopropylethylamine (96 uL, 0.55 mmol) in dichloromethane (1 mL) was cooled to 0° C. and methanesulfonyl chloride (39 uL, 0.5 mmol) was added. The mixture was allowed to warm to rt over 15 h, and then water was added. The resulting mixture was extracted with dichloromethane. The organic extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (500 uL) and dioxane (500 uL), and then sodium hydroxide (2 M, 190 uL, 0.38 mmol) was added. The mixture was heated to 60° C. and 3 drops of aqueous sodium hydroxide (50%) were added. After stirring a further 30 min, the mixture was cooled to rt. Dilution with water was followed by acidification with aqueous citric acid (10%) and then two extractions with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient 100% hexanes to 70% hexanes:30% ethyl acetate) to provide N-(5-bromo-2-ethoxypyridin-3-yl)methanesulfonamide (32.1 mg, 0.11 mmol, 43% yield) as a colorless film. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.89 (d, 1H), 6.75 (br s, 1H), 4.42 (q, 2H), 3.05 (s, 3H), 1.41 (t, 3H); MS (EI) for C8H11BrN2O3S: 295, 297 (Br isotopes, MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C(Cl)Cl>[OH:20][C:17](=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])[CH2:18][CH3:19]
Reactant: CCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Meldrum's acid (10 g, 69.4 mmol) in CH2Cl2 (170 mL) was cooled to 0° C. Pyridine (11.2 ml, 138.8 mmol) and propanoyl chloride (10.1 mL, 76.3 mmol) were added via syringe. The resulting solution was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was diluted with CH2Cl2 and washed with aq HCl (15 mL conc HCl in 200 mL water, 1×) and water (1×). The organic solution was dried over Na2SO4 and concentrated to give a dark red solid.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C(C)=CC=CC=1.Cl>[CH3:10][CH:9]([NH:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1)[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)Nc1nccnc1Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1nccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-(1-methylethylamino)pyrazine (PREPARATION 6, 1.6 g) and piperazine (4.3 g) in xylene (10 ml) is refluxed for 26 hr. The mixture is cooled to 0° and diluted with concentrated hydrochloric acid (8 ml). The xylene is decanted and ether is added and also decanted from the salts. The salts are diluted with excess aqueous sodium hydroxide (5%) and dichloromethane. The phases are separated. The aqueous phase is extracted three more times with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated to give a liquid mixture which is flash chromatographed on silica gel eluting with methano/chloroform (5/95). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.27, 1.83, 3.04, 4.12, 4.78, 7.49 and 7.72 δ.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][N:6]=1)([O-])=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29]N>C(O)C>[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][N:6]=1
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Reactant: NCCSCc1nccs1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3nccs3)[nH]c2=O)ccn1
Yield: 41 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone and 2-(2-thiazolylmethylthio) ethylamine was heated under reflux in ethanol for 18 hours. The solid which crystallised out on cooling was purified by column chromatography on silica gel and recrystallisation from 2-propanol-ethanol to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 105.5-106.5° in 41% yield. The latter compound was heated under reflux in 2N hydrogen chloride in ethanol for 24 hours to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone monohydrochloride, m.p. 169-173°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:17]([NH2:19])[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:17]([NH:19][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccs1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccs1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(thiophen-2-yl)-quinolin-3-yl)ethanamine (0.078 g, 0.286 mmol), 6-chloropurine (0.053 g, 0.344 mmol, 1.2 eq) and DIEA (0.58 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(7-fluoro-2-(thiophen-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.62 (s, 1 H), 8.43 (s, 1 H), 8.37 (s, 1 H), 8.00-8.07 (m, 1 H), 7.62-7.73 (m, 3 H), 7.43-7.51 (m, 1 H), 7.18 (m, 1H), 1.78 (d, J=7.04 Hz, 3 H), 1 H), Mass Spectrum (ESI) m/e=391 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: OCc1ccccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a mixture of 4-amino-2-chloro-phenol (1.0 g, 6.96 mmol), 2-hydroxymethylpyridine (1.52 g, 13.92 mmol), Ph3P (3.65 g, 13.92 mmol) in THF (30 ml) was added DIAD (2.74 ml, 13.92 mmol). The reaction mixture was stirred overnight and then concentrated in vacuo, and dissolved in EtOAc (100 ml). The resulting solution was extracted with 1N HCl (60 ml); the aqueous layer was washed with EtOAc (2×60 ml), then basified with solid NaHCO3. The mixture was extracted with EtOAc (2×100 ml) and the combined EtOAc extracts were washed with brine (1×40 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash column to give 1C (0.54 g, 33%) (50%–80% EtOAc-Hexanes). Analytical HPLC retention time=0.61 min. (YMC S5 ODS column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) and a LC/MS M++1=235.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:41]=[CH:40][C:17]([NH:18]/[C:19](=[C:26]3\[C:27](=[O:39])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=4)/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH:18]/[C:19](=[C:26]3\[C:27](=[O:39])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=4)/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:40][CH:41]=2)[CH2:10][CH2:11]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCN(CCc2ccc(N/C(=C3\C(=O)Nc4cc(OC)c(OC)cc43)c3ccccc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CCN3CCC(C(=O)O)CC3)cc1)c1ccccc1)C(=O)N2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.4 g of 3-(Z)-(1-{4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone are dissolved in 8.0 ml of ethanol and 2.0 ml of 1N sodium hydroxide solution are added. The mixture is stirred for 1 hour at 50° C. 2.0 ml of 1N HCl are added to the clear solution and the precipitate formed is suction filtered. The precipitate is washed with water and ethanol and dried in vacuo at 100° C.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([C:20]2[C:29]3[O:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:26]([CH3:36])[C:25](=[O:37])[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:13][CH2:12]1)[CH3:3]>CO>[ClH:1].[OH:19][CH:18]([C:20]1[C:29]2[O:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH3:36])[C:25](=[O:37])[C:24]=2[CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:2][CH3:3])[CH2:12][CH2:13]1
Reactant: CCOc1ccccc1N1CCN(CC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Agent: Cl
Solvent: CO
Product: CCOc1ccccc1N1CCN(CC(O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1

Procedure:
This compound was prepared according to Example 17, but starting from the compound prepared in Example 3 rather than that prepared in Example 1. m.p. 241°-242° C. (methanol).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([CH2:27][O:28][CH2:29][CH2:30][O:31]CC1C=CC=CC=1)([CH2:15][O:16][CH2:17][CH2:18][O:19]CC1C=CC=CC=1)[CH3:14])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2].[Pd]>[OH:31][CH2:30][CH2:29][O:28][CH2:27][C:13]([CH2:12][O:11][CH2:10][CH2:9][OH:8])([CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14]
Reactant: CC(COCCOCc1ccccc1)(COCCOCc1ccccc1)COCCOCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(COCCO)(COCCO)COCCO
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A mixture of 1,1,1-tris(benzyloxyethoxymethyl)ethane (13.9 g, 0.027 mol) and palladium hydroxide on carbon, Pd content 20% (2.8 g) in 100 mL of methanol was hydrogenated at 50 psi in a Parr apparatus for 4 hrs. The catalyst was removed by filtration through Celite and the filtrate was evaporated under reduced pressure to give 1,1,1-tris(hydroxyethoxymethyl)ethane (6.7 g, 0.026 mol, 99%).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[F:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([CH3:23])[N:13]=[C:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O1CCCC1.CO.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:13][C@H:12]2[CH3:23]
Reactant: Cc1nc2ccccc2c2ccc(F)cc12
Agent: C[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@@H]1Nc2ccccc2-c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 192 h
Yield: 95.3 %

Procedure:
To a stirred suspension of lithium borohydride (8.25 g, 0.378 mole) in a mixture of toluene (94.7 niL) and tetrahydrofuran (9.46 mL) kept under nitrogen and at 0° C. was added dropwise chlorotrimethylsilane (96.1 nmL). Additional tetrahydrofuran (30 mL) and toluene (105 mL) were added to rinse the glassware. (R)-2-methyl-CBS-oxazaborolidine (56.8 mL) was added dropwise at room temperature. The mixture was cooled to 0° C. and solid 8-fluoro-6-methylphenanthridine (40 g, 0.189 mole) was added in two portions over a 10 minute and 5 minute period, respectively. The cooling bath was removed, the flask walls rinsed with toluene (60 mL) and the brown slurry was stirred at room temperature. Aliquots were taken at regular intervals to monitor the progress of the reaction. After 8 days the conversion reached 97% . The reaction mixture was cooled to 0° C., treated dropwise with 10% aqueous citric acid (100 mL) under vigorous stirring to control foaming. Ethyl acetate was added (800 mL) followed by more 10% aqueous citric acid (300 mL) and then methanol (300 mL) to redissolve the precipitate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and evaporated to dryness to provide 38.4 g (95% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:13].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[CH:6]([C:5]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]([O:1][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[C:3]([CH3:13])[CH:4]=1)=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: Cc1cc(C=O)cc([N+](=O)[O-])c1O
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1c(C)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-3-methyl-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a tan solid: 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.97 (s, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.09 (d, J=1.5 Hz, 1 H), 4.82 (q, J=6.8 Hz, 1H), 3.62 (s, 3H), 2.42 (s, 3H), 1.52 (d, J=6.8 Hz, 3H). ESI-MS: m/z 268.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.CON(C)[C:13](=[O:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[Cl-].[NH4+].O>O1CCCC1>[Cl:8][C:7]1[C:2]([C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: Clc1cnc(Br)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ncc(Cl)cc1Cl
Temperature: -20 °C
Yield: 59.6 %

Procedure:
To 35.1 g of 2-bromo-3,5-dichloropyridine in 10 ml of tetrahydrofuran, 116.3 ml of a 1.3 M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 15 minutes. Then, to the reaction mixture, 15.0 g of N-methoxy-N-methyl-2-(tert-butoxycarbonylamino)acetamide in 114 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at the same temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of saturated aqueous ammonium chloride and 100 ml of water and extracted with ethyl acetate (200 ml×2), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:10 to 3:7) as the eluent to obtain 12.5 g of the desired product as pale yellow crystals.
Reaction SMILES: [C:1](OC(OCC)OCC)(=O)C.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:25]([NH2:30])[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:31]([CH2:32][CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:1]=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc3c(c2)ncc2ncn(CCOc4ccccc4)c23)cc1
Yield: 101.1 %

Procedure:
Under a nitrogen atmosphere, diethoxymethyl acetate (3.0 mL, 18 mmol) was added dropwise to a solution of 7-benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine (3.0 g, 7.8 mmol) in toluene (30 mL), and the reaction was heated at reflux for three hours. The reaction mixture was concentrated under reduced pressure until a small volume of solvent remained. Hexanes were added, and the resulting mixture was cooled for 20 minutes in a refrigerator. A precipitate formed which was isolated by filtration, washed with hexanes, and dried overnight under reduced pressure to provide 3.12 g of 7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline as a solid.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[N:12]1[CH:11]=[CH:10][CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)c1cccnc1Cl
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: O
Solvent: COCCOC
Product: CCOC(=O)c1cccnc1-c1ccncc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of ethyl 2-chloronicotinate (16.2 g), pyridine-4-boronic acid (12.9 g), sodium carbonate (27.8 g), tetrakis(triphenylphosphine)palladium(0) (5.04 g), water (50.0 mL) and DME (250 mL) was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (14.1 g).