Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[C:44]([NH:43][CH2:42][CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:50])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:48]([CH3:49])[CH:47]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)NCCOc1cc(C)c(Br)c(C)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCNC(C)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and N-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)acetamide following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.50 min; Mass spectrum (ESI+): m/z=548 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([I:9])=[CH:4][C:3]=1[OH:10].N1C=CC=CC=1.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[S:18]([O:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([I:9])=[CH:4][C:3]=1[O:10][S:18]([C:21]([F:22])([F:23])[F:24])(=[O:17])=[O:19])(=[O:19])=[O:17]
Reactant: Oc1cc(I)c(I)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc(I)c(I)cc1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a flame-dried round-bottomed flask was added 1,2-dihydroxy-4,5-diiodobenzene (1 equiv., 7.85 mmol, 2.84 g), CH2Cl2 (55 mL), and pyridine (5 equiv., 39 mmol, 3.10 g, 3.16 mL). The solution was cooled to 0° C. and Tf2O (2.2 equiv., 17.3 mmol, 4.88 g, 2.91 mL) was added dropwise via syringe over 10 min. The reaction was stirred for 6 h while warming to ambient temperature, then cooled to 0° C. and quenched with H2O (30 mL). The separated aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried with MgSO4 and filtered through a tall pad of silica. The pad was washed carefully with CH2Cl2 to avoid the elution of impurities, and the filtrate was concentrated in vacuo to afford 4,5-diiodo-1,2-phenylene bis(trifluoromethanesulfonate) (4.90 g, 7.82 mmol, quantitative) as an off-white solid. The product is optionally purified by column chromatography (10% EtOAc/Hex). TLC Rf=0.60 (10% EtOAc/Hex); Melting point 46.5-47.7° C.; 1H NMR (400 MHz): δ 7.91 (s, 2H); 13C NMR (100 MHz): δ 139.6, 133.4, 118.5 (q, JC,F=321.0 Hz), 108.0. FTIR: 1429, 1335, 1215, 1125, 1105, 868, 788, 745, 689 cm−1. HRMS-ESI: calc. for C8H2F6I2NaO6S2 (M+Na)+: 648.7184. found: 648.7164.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9](Br)([Br:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)(C)C.[Sn](Cl)Cl>O>[CH2:1]([O:3][P:4]([CH:9]([Br:17])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)C(Br)(Br)C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(C)O
Product: CCOP(=O)(OCC)C(Br)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Combine t-butyl diethylphosphonodibromoacetate (75.6 g, 184 mmol) and isopropanol (190 mL). Cool to 0° C. Add a solution of tin (II) chloride (33.2 g, 175 mmol) in water (190 mL). After the addition is complete, warm to ambient temperature. After 1 hour, extract the reaction mixture three times with chloroform. Combine the organic layers and extract with water, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]([C:22](O)=[O:23])[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH:25][N:26]1C2C=CC=CC=2N=N1.[N:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C.ClCCl>[N:35]1([CH2:41][CH2:42][NH:43][C:22]([C:13]2[NH:14][C:15]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[C:2](=[N:26][OH:25])[CH2:3][CH2:4]4)[N:12]=2)=[O:23])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1nc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of the product of Description 1 (105 mg, 0.33 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol) and N-cyclohexylcarbodiimide-N′-methyl polystyrene (500 mg, 0.66 mmol, resin loading 1.32 mmol/g) in DMF (2 ml) was stirred at room temperature for 30 minutes. A solution of 2-morpholin-4-yl-ethylamine (43 mg, 0.33 mmol) in dichloromethane (0.5 ml) was added and the mixture stirred at room temperature for 24 hours. The mixture was filtered through an SCX cation exchange resin column eluting with methanol followed by 10% 0.880 ammonia solution in methanol to elute the product. Following concentration, the residue was purified by silica gel chromatography eluting with a 1:9:90 mixture of 0.880 ammonia solution: methanol:chloroform gave the title compound (65 mg, 46%) as a yellow solid; MS(AP+) m/e 432 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8](C)[C:9](=O)OC(C)(C)C)=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[S:20]([CH3:23])(=[O:22])=[O:21].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH3:9])=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1N(CCN1CCOCC1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzyl-(methyl)carbamate (114 mg, 0.249 mmol) was dissolved in dry DCM (6 ml), and HCl 4M in dioxane (500 μl, 2.000 mmol) was added. The reaction was stirred at RT for 24 hours. The solvent was evaporated under vacuum and N-(2-methoxy-5-((methylamino)methyl)phenyl)-N-(2-morpholinoethyl)methanesulfonamide was obtained as hydrochloride salt (89 mg, 0.249 mmol, 100% yield, MS/ESI+ 358.1 [MH]+) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]\[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)/[C:4]([O:6]CC)=[O:5].Cl>O1CCCC1.CO.[OH-].[Na+]>[CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]\[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:16][CH:17]=1)/[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Ethyl E-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (1.27 g) was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred for 2 hours at room temperature. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (1.02 g, yield: 85%) as colorless crystals. m.p. 128-129° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2cccc(F)c2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2F)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogen carbonate (1.33 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,3-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.72 g, 84%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.C[N:17](C)[CH2:18][CH2:19][CH2:20]N=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(N)C#C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[NH:17][CH2:18][C:19]#[CH:20])[CH2:11]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: C#CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.5 g (2.48 mmol) boc-azetidine-3-carboxylic acid in 5 mL DCM were added 0.52 g (2.73 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.4 g (2.98 mmol) 1-hydroxybenzotriazole hydrate and 0.9 mL (5.47 mmol) DIPEA, and the reaction was stirred at room temperature for 30 minutes. 0.19 mL (2.73 mmol) propargylamine was added and the reaction was stirred for 16 hours at room temperature. 5 mL DCM was added and the mixture was washed with 10 mL aqueous HCl (1 M), then 10 mL aqueous NaHCO3 (1 M) and 10 mL brine. The organic layer was dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:23][CH:22]=4)=[O:19])=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:34][I:35]>CN(C=O)C>[I-:35].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N+:28]5([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:23][CH:22]=4)=[O:19])=[CH:15]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)C1=Cc2cc(-c3ccc(F)cc3)ccc2CC1
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(F)cc5)ccc4CC3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In DMF (3 ml) was dissolved 7-(4-fluorophenyl)-N-[4-(piperidinomethyl)phenyl]-3,4-dihydronaphthalene-2-carboxamide (500 mg), and to the mixture was added methyl iodide (212 μl). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-[4-[7-(4-fluoro-phenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]-1-methylpiperidinium iodide (Compound 17) (610 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C1CCNC1
Product: Nc1nc(N2CCCC2)c2nc[nH]c2n1

Procedure:
2-Amino-6-chloropurine (Sigma, lot #69F4064, 5.0 g, 29.5 mmol) was stirred in pyrrolidine (Kodak, lot #B161, 30mL) at 80° C. for 24 hours. The solvent was evaporated to a gold solid which was recrystalized from methanol to yield 3.41 g (16.7 mmol, 58%); mp=265°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].[Cu][C:26]#[N:27]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccc(F)cc3)cccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(Oc3ccc(F)cc3)cccc2c1O
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A mixture of 1-bromo-8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (400 mg, 1.02 mmol) and copper(I) cyanide (183 mg, 2.04 mmol) in anhydrous dimethylformamide (4 mL) was refluxed for ten minutes before it was cooled to room temperature and quenched with water. The slurry was stirred with chloroform/isopropanol (3:1, 70 mL) and water for ten minutes and filtered. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane to give the title compound as a white solid (158 mg): MS: (+) m/z 339.07 (M+1).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[Cl:12]C(Cl)(Cl)C(O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[ClH:12].[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:1]2[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1ccc(COC(=O)C(Cl)(Cl)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Product: Cl
Yield: 56.4 %

Procedure:
To 7 liters of toluene were added 695 grams (4.4M) of ethyl nipecotate, 1304 grams (4.8M) of p-methoxybenzyl trichloroacetate, and 660 grams (4.8M) of potassium carbonate. The mixture was refluxed for 72 hours under a nitrogen atmosphere after which it was cooled, and the solvent was removed in vacuo. The resulting oil was dissolved in chloroform, and the solution was washed with 10% aqueous potassium carbonate followed by 10% aqueous hydrochloric acid. The solution then was dried over sodium sulfate and concentrated in vacuo. The resulting oil was triturated with ethyl ether, yielding 783 grams of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.[O:31]=[C:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:32]3([OH:31])[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:33]3)[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (5.0 g) and N,N,N′,N′-tetramethylethylenediamine (4.46 mL) in tetrahydrofuran (80 mL) at −78° C. was added 2.5 M of n-Butyllithium in THF (17 mL). The solution was stirred at −78° C. for 15 mins then the temp was raised to −40° C. until the solution became clear and dark red (indicating full lithiation). The solution was lowered back to −78° C. and tert-butyl 3-oxopiperidine-1-carboxylate (8.64 g) in 10 mL THF was added slowly over 5 minutes and stirred for 1.5 hrs then quenched with water. The reaction mixture was diluted with ethyl acetate and extracted with a saturated ammonium chloride solution. The organic layer was dried, filtered and concentrated. Any remaining starting material was removed by trituration with hot ether to afford the crude product tert-butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylate as an orange oil in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[OH:25])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Reactant: O=C(O)c1ccccc1O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3ccccc3O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 2-hydroxybenzoic acid as brown solid (56%). MS 452 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[Si:21]([O:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[Si:21]([O:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH:43][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1)([C:34]([CH3:35])([CH3:36])[CH3:37])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)[Si](OCc1cccc(N)c1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=S)c1cnc(C)nc1Nc1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 50 °C
Yield: 103.4 %

Procedure:
A solution of 2.32 g (10 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 30 ml of 1,4-dioxan was treated with 1.4 ml (10 mmol) of triethylamine and 4.7 g (13 mmol) of 3-(tert-butyldiphenylsilyloxymethyl)aniline. The mixture was heated to 50° C. for 18 hours and then evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 5.6 g (100%) of ethyl 4-[3-(tert-butyldiphenylsilyloxymethyl)anilino]-2-methylthiopyrimidine-5-carboxylate as a colorless oil. [Mass spectrum (ESI) MH+ =558].
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)C(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A solution of N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (1.08 g, 3.57 mmol) in MeOH (30 mL) was treated with hydrazine hydrate (1.00 g, 19.98 mmol) followed by Raney Nickel (0.300 g, 5.11 mmol) and stirred at RT for 3 h. The solids were removed via filtration through diatomaceous earth, washed with DCM and MeOH and the filtrate concentrated to dryness to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (900 mg, 93%) as an off-white solid. MS (ESI) m/z: 273.2 (M+H+).
Reaction SMILES: [CH2:1]([NH2:17])[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][CH3:16].[ClH:18].[N:19]#[C:20][NH2:21]>C(O)CCC>[Cl-:18].[CH2:1]([NH:17][C:20]([NH2:21])=[NH2+:19])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: N#CN
Reactant: Cl
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCNC(N)=[NH2+]
Product: [Cl-]
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
Hexadecylamine (3 g, 12.4 mmol) was dissolved in 1-butanol (10 ml) and 37% hydrochloric acid (1.23 g, 12.4 mmol) added. The solution was warmed to 95° C. and cyanamide (0.522 g, 12.4 mmol) dissolved in 1-butanol (20 ml) added dropwise with stirring over 10 minutes. The solution was stirred at 95° C. for a further 2 hours. Solvent was removed and the crude product crystallised from ethyl acetate to give a white solid of N-hexadecylguanidinium chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-Hydroxyphenyl)acetonitrile (Step A, 5 g, 37 mmol) and diisopropyl azodicarboxylate (DIAD, 3.38 g, 16.7 mmol) in dry THF (20 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (2.25 g, 16.5 mmol) and triphenylphosphine (TPP, 4.3 g, 16.4 mmol) in THF (30 ml) at 0° C. under argon. The reaction mixture was stirred at room temperature for 16 hours or until all the starting material is consumed. Silica gel (25 g) was added to the mixture, solvents were removed under reduced pressure, loaded on silica gel column and eluted with methylene chloride:hexane (1:1) to give light yellow crystalline solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][CH2:7][C:8]1[C:17]([CH2:18]Br)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1>C(O)C>[Br-:6].[CH2:1]([N+:3]1([CH2:4][CH3:5])[CH2:18][C:17]2[CH:16]=[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=[CH:9][C:8]=2[CH2:7]1)[CH3:2]
Reactant: CCNCC
Reactant: BrCc1cc2ccccc2cc1CBr
Solvent: CCO
Product: CC[N+]1(CC)Cc2cc3ccccc3cc2C1
Product: [Br-]

Procedure:
An ethanolic diethylamine solution (100 ml) was added dropwise to 2,3-bis(bromomethyl)naphthalene (20 g) in ethanol (10 ml) kept at 0°. The precipitate which formed was filtered and recrystallised from propan-2-ol/water to give 2,2-diethylbenz[f]isoindolinium bromide m.p. 228°.