Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:36])[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28](C)(C)C(C)(C)[O:26]3)=[C:21](C=O)[CH:20]=2)[N:11]=1)(C)(C)C.[BH4-].[Na+].Cl>CO>[OH:26][B:25]1[C:22]2[CH:23]=[CH:24][C:19]([O:18][C:12]3[N:11]=[C:10]([N:9]([CH2:8][CH2:7][OH:6])[CH3:36])[CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:20][C:21]=2[CH2:28][O:29]1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)c1ccc(C#N)c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc3c(c2)COB3O)n1
Reaction time: 8 h
Yield: 17.4 %

Procedure:
To a clear solution of 6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (11) (485 mg, 0.903 mmol) in MeOH (anhydrous, 100 mL) was slowly added NaBH4 (101 mg, 2.65 mmol). The reaction was stirred at room temperature for 4 hours, before the addition of HCl solution (1 M, 60 mL). The stirring was kept at room temperature overnight. Then the solution was slowly evaporated in vacuo. Purification was accomplished by reverse phase Biotage with 10%-100% MeOH/H2O gradient to afford 51 mg (13.8% yield) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.24 (s, 1H), 7.16 (dd, J=7.8, 2.0 Hz, 1H), 6.43 (br. s., 1H), 4.98 (s, 2H), 3.90 (br. s., 1H), 3.47 (br. s., 2H), 3.39 (s, 2H, masked), 2.95 (br. s., 3H); HPLC: 98.18% (220 nm), 99.15% (254 nm), 99.16 (MaxPlot).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([CH2:29][NH2:30])[OH:28]>C(#N)C.C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH:30][CH2:29][CH2:27][OH:28])[CH2:13][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reactant: NCCO
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CNCCO)CC1
Temperature: 50 °C

Procedure:
To a solution of toluene-4-sulfonic acid trans-4-(tert-butyldimethylsilanyloxy)-cyclohexylmethyl ester (600 mg, 1.50 mmol) in acetonitrile (15 mL) was added ethanolamine (2.0 mL, 25 eq). The solution was heated to 50° C. overnight. The reaction was diluted with DCM (200 mL), washed with saturated aqueous sodium bicarbonate and brine, and dried over potassium carbonate. Solvent was removed to give crude title intermediate (0.44 g) as a yellow oil. (m/z): [M+H]+ calcd for C15H33NSiO2, 288.3; found 288.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.Cl.[C:42]([O:46][C:47](=[O:50])[CH2:48][NH2:49])([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:42]([O:46][C:47](=[O:50])[CH2:48][NH:49][C:8]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1ncccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1ncccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.5 %

Procedure:
To a solution of 3-hydroxypicolinic acid (0.20 g, 1.44 mmol) in DMF (5 mL) at 0° C. under N2 is added diisopropylethylamine (DIPEA) (0.75 ml, 4.3 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (0.412 g, 2.9 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.019 g, 0.14 mmol). The resulting mixture is stirred for 5 min before glycine tert-butyl ester HCl (0.36 g, 2.9 mmol) is introduced. The resulting solution is stirred at room temperature for 3 days then concentrated under reduced pressure. The reaction mixture is diluted with EtOAc then washed with 1M HCl, sat. NaCl, and the organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to a crude oil that is purified over silica (EtOAc/heptane 1:4) to afford 0.078 g (22% yield) of the desired compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.80 (1 H, s), 8.39 (1 H, br s), 8.02 (1 H, dd, J=4.4, 1.5 Hz), 7.27 (1 H, dd, J=8.8, 4.4 Hz), 7.25 (1 H, dd, J=8.4, 1.5 Hz), 4.06 (2 H, d, J=5.5 Hz), 1.44 (9 H, s). HPLC-MS: m/z 197 [M-tBu]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:18])(C(F)(F)F)[CH2:10][C:9]=2[Cl:19])[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.[Br:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:18])=[CH:10][C:9]=3[Cl:19])[CH:5]=[C:4]([C:20]([F:21])([F:22])[F:23])[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cc(C2=C(Cl)CC(Cl)(C(F)(F)F)C=C2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(2,4-dichloro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.61) (1.50 g, 4.58 mmol) and commercially available 3-bromo-benzene-boronic acid (1.01 g, 5.03 mmol) according to the general procedure IVb. Obtained as a white solid (1.26 g, 61%). MS (EI) 447.9 [(M)+]; mp 124.5° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][CH2:6][C:7]1[N:8]=[C:9]([N:12]=[C:13]([NH2:15])[NH2:14])[S:10][CH:11]=1)#[N:2].Cl.[CH2:17]=[O:18]>>[NH2:15][C:13](=[N:12][C:9]1[S:10][CH:11]=[C:7]([CH2:6][S:5][CH2:4][CH2:3][C:1](=[NH:2])[O:18][CH3:17])[N:8]=1)[NH2:14]
Reactant: N#CCCSCc1csc(N=C(N)N)n1
Reactant: C=O
Agent: Cl
Product: COC(=N)CCSCc1csc(N=C(N)N)n1

Procedure:
reacting the compound produced in step (b) with hydrogen chloride and methanal to obtain the compound methyl 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]-methyl]thio]propionimidate isolating and drying said compound; and
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[O:14]C1CCCCO1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([O:3][C:4](=[O:21])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(C)ccc1OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)/C=C/c1cc(C)ccc1O
Yield: 71 %

Procedure:
A solution of 193.7 g 3-[5-methyl-2-(tetrahydro-pyran-2-yloxy)-phenyl]-acrylic acid ethyl ester (Bunce, R., Moore, J., Org. Prep. Proc., 29(3), 293 (1997)) and 2 g p-toluenesulfonic acid in 2.5 l of ethanol was stirred at room temperature for 24 hours. Then the reaction mixture was concentrated and the residue was diluted with ether, washed with saturated sodium bicarbonate and brine, dried and evaporated to dryness. The resulting yellow solid was recrystallized to yield 97.7 g of colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:32])[N:6]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.NN>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH2:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:32])[N:6]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1nc(SCCN2C(=O)c3ccccc3C2=O)nc2c1nc(O)n2Cc1ccccc1
Agent: NN
Solvent: O
Product: NCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 7 %

Procedure:
6-Amino-9-benzyl-8-hydroxy-2-(2-phthalimidoethylthio)purine (78 mg, 0.18 mmol) was suspended in 1M hydrazine monohydrate (10 ml). The suspension was stirred at room temperature for 9 hours. The reaction mixture was evaporated in vacuo to dryness and to the residue was added 2N hydrochloric acid. Insoluble materials were filtered off and the filtrate was neutralized with 28% aqueous ammonia and extracted with ethyl acetate. The organic layer was dried on magnesium sulfate and evaporated in vacuo to dryness to give the subject compound (4 mg, yield 7%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])=[CH:5][CH:4]=1.[O:17]=[C:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1>C1COCC1.C1(C)C=CC=CC=1>[OH:17][C@:18]1([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:15]=[CH2:16])=[CH:5][CH:4]=2)[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1
Reactant: C=Cc1ccccc1-c1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=Cc1ccccc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Magnesium (0.110 g, 4.58 mmol) turnings were stirred in a round bottom flask under nitrogen for 30 min. to cause scratching of the surface of the magnesium. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-2-vinylbiphenyl (Intermediate 1, 1.13 g, 4.36 mmol) in THF (30 mL), was added dropwise at reflux with vigorous stirring. The Grignard solution (40 mL) was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (Intermediate 2, 1.0 g, 3.53 mmol) in toluene (30 mL) at 0° C. and stirred for 1 hr and then quenched with a saturated NH4Cl solution. The aqueous layer was extracted with DCM. The combined organics were washed with brine and dried over MgSO4, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-33% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (0.5 g, 30% yield) as a yellow oil. LCMS: rt=1.92 min. [M+Na]+=490; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 9H) 0.88-1.14 (m, 2H) 2.38-2.50 (m, 1H) 2.74 (dd, J=13.58, 10.22 Hz, 1H) 3.89 (d, J=11.60 Hz, 2H) 3.76-3.84 (m, 1H) 3.86 (s, 3H) 4.00 (dd, 1H) 4.23 (s, 1H) 4.24-4.28 (m, 1H) 4.55-4.66 (m, 1H) 5.20 (dd, J=10.9, 1.22 Hz, 1H) 5.71 (dd, J=17.55, 1.07 Hz, 1H) 6.70 (dd, J=17.40, 10.99 Hz, 1H) 7.28 (dd, 1H) 7.34 (dd, J=7.17, 1.68 Hz, 1H) 7.37 (d, J=8.55 Hz, 2H) 7.54 (d, J=8.24 Hz, 2H) 7.65 (d, J=7.32 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]([F:15])([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]=2[CH:3]=1.[O:19]=[C:20](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:15][C:7]1([F:14])[O:6][C:5]2[CH:16]=[C:17]([F:18])[C:2]([N:1]=[C:20]=[O:19])=[CH:3][C:4]=2[N:9]([CH2:10][C:11]#[CH:12])[C:8]1=[O:13]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N=C=O)cc21
Reaction time: 8 h

Procedure:
To 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5.1 g, 19.91 mmol) in dry toluene was dropwise added diphosgene (2.64 ml, 21.90 mmol) in dry toluene. The resulting mixture was stirred overnight at reflux. The mixture was concentrated and chased with toluene and used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@@H:34]([CH2:37][CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@H:34]([CH2:35][OH:36])[CH2:37][CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC[C@H](N)CO
Product: CC[C@@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (S)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+]539.2447, observed 539.2449.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23].CN([CH:29]=[O:30])C>C1COCC1>[CH3:18][C:15]1([CH3:19])[O:14][C@@H:13]([CH2:12][O:11][C:10]2[CH:20]=[CH:21][C:7]([CH:29]=[O:30])=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[CH2:17][O:16]1
Reactant: CC1(C)OC[C@H](COc2ccc(Br)c(C(F)(F)F)c2)O1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc(C=O)c(C(F)(F)F)c2)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of nBuLi in hexanes (6.76 mL, 1.6 M in hexanes) was added dropwise to a solution of (S)-4-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (127; 3.20 g, 9 mmol) in THF (50 mL) at −78° C. over a period of 30 min. After stirring for additional 10 min, DMF (1.4 mL) was added dropwise over a period of 10 min. The resulting reaction mixture was warmed to room temperature and stirred for 30 min. It was then quenched with water and extracted by EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:EtOAc=50:1) to afford (S)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-(trifluoromethyl)benzaldehyde 128 (2.3 g, 84%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([F:42])([F:41])[F:40]>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][CH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([F:41])([F:40])[F:42]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
N-Bromosuccinimide (1.04 g, 5.83 mmol) and benzoyl peroxide (0.12 g, 0.49 mmol) were added to a solution of ethyl 4-methyl-3-(trifluoromethyl)benzoate (1.06 g, 4.56 mmol) in carbon tetrachloride (25 mL). The reaction mixture was heated at reflux overnight. After it was cooled to room temperature, it was diluted with dichloromethane (50 mL), and washed with water (20 mL). The aqueous layer was extracted with dichloromethane (20 mL). It was dried over Na2SO4 and concentrated. It was purified by prep-TLC (Hexanes:ethyl acetate=10:1) to give the product as an oil (0.60 g, 44%) 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=1.6 Hz, 1H), 8.20 (dd, J=4.8, 1.6 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 4.64 (s, 1H), 4.40 (q, J=7.2 Hz, 2 H), 1.40 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:27][CH2:28][OH:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH2:28][OH:29])[CH2:18]1
Reactant: OCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CCO)C3)c2n1

Procedure:
Prepared similarly to Example 1 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (for example, as prepared for Intermediate 18) and 2-bromoethanol (commercially available, for example, from Aldrich).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1nccn1Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
148 g (936 mmol) of 1-benzyl-1H-imidazole are suspended in 480 ml of acetonitrile and, at −20° C., 120 ml (87.1 g; 860 mmol) of triethylamine are added. Over a period of 15 minutes, 211.2 ml (239 g; 2208 mmol) of ethyl chloroformate are then added dropwise. The reaction mixture is stirred at −20° C. for 10 minutes. After warming to 15 to 20° C., the reaction mixture is stirred for 18 h and then concentrated in vacuo. Water, a saturated sodium chloride solution and a saturated sodium bicarbonate solution are added to the residue, and the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution and, after drying with magnesium sulfate, concentrated in vacuo. The residue is subjected to a fractional distillation under high vacuum (boiling point=173 to 181° C., pressure=1.7 to 1.2 mbar).
Reaction SMILES: [CH:1]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([C:6]2[CH:5]=[CH:4][C:3]([O:26][C:21]3[CH:22]=[CH:23][C:24]([NH2:25])=[C:19]([CH3:18])[CH:20]=3)=[CH:2][CH:1]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1cc(O)ccc1N
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)ccc1N
Temperature: 25 °C
Reaction time: 28 h
Yield: 42.9 %

Procedure:
To a 250 mL flask equipped with stirrer, condenser, under nitrogen atmosphere, was added 20 g (0.070 mol) of 4,4'-dichlorodiphenylsulfone, 12.8 g (0.104 mol) of 3-methyl-4-aminophenol, 15.5 g (0.112 mol) of potassium carbonate, and 130 mL of dimethylformamide. The resulting mixture was stirred at room temperature for 24 hours and at 125° for 28 hours. It was cooled and concentrated. The concentrated material was dissolved in 400 mL of toluene and washed with 4% sodium hydroxide, followed by water and brine washes. The organic layer was dried over sodium sulfate, concentrated, and chromatographed through 350 g of florisil column. Elution with hexane/ethylacetate (8/2) afforded 11.2 g (0.030 mol) of a yellow solid; mp 200° D.
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].[CH:17]([O:20][CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]>>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13].[CH:17]([O:20][CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC[Mg]Br
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: CC(C)OC(C)C
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 70 ml of a diisopropyl ether (chain ether solvent) solution containing 0.066 mol of suspended ethyl magnesium bromide was charged to the reaction vessel. Meanwhile, 0.060 mol of bromopentafluorobenzene and 20 ml of diisopropyl ether (chain ether solvent) were charged to the dropping funnel. Then, the diisopropyl ether solution of bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 2 hours at room temperature, and the reaction solution was stirred for 12 hours at room temperature. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a colorless diisopropyl ether solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 94.3 mol % based on bromopentafluorobenzene.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14].P(Cl)(Cl)Cl.ClCCl>>[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH:14][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1O
Temperature: 137 °C

Procedure:
The method disclosed in U.S. Pat. No. 3,079,297 to Shraufstatter et al with minor variations was utilized. A boiling solution of salicylic acid (1.03 g, 7.46 mmol) and 2-chloro-4-nitroaniline (1.29 g, 7.46 mmol) in xylenes (20 mL) was treated dropwise with a solution of phosphorous trichloride in dichloromethane 2.0M, 1.50 mL, 0.40 equiv.), and the resulting solution was refluxed (137° C.) for four hours. The solution was cooled to about 125° C. An oily residue covered the bottom and sides of the reaction vessel. The hot reaction solution was transferred by glass pipette to a beaker and was allowed to cool to room temperature while being stirred rapidly. The product separated, was collected by filtration, and washed with hexanes, then recrystallized from ethanol. The title compound was obtained, MP 218-220° C. (dec.). 1HNMR (500 MHz, DMSO-d6): δ 7.02 (m, 1H, H3), 7.07 (m, 1H, H5), 7.49 (m, 1H, H4), 8.04 (m, 1H, H6), 8.28 (m, 1H, H5′), 8.41 (m, 1H, H3′), 8.85 (m, 1H, H6′), 11.8 (s, 1H, NH), 12.34 (s, 1H, OH).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-].[Na+].Cl[CH2:15][CH2:16][OH:17]>O>[OH:17][CH2:16][CH2:15][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCCO

Procedure:
Vanillin (15.2 g, 0.01 m), water (70 mL), and sodium hydroxide (5.0 g, 0.0125 m) are mixed and stirred for a few minutes until solution is completed. 2-Chloroethanol (9.7 g, 0.012 m) is added and the reaction mixture heated at reflux for 16 hours and then cooled. The solid product is collected by filtration, washed with water, dried, and finally recrystallized from toluene. The yield is 13.0 g (69.9% of the theoretical yield).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9])([CH3:4])[CH3:3].O.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Methyl 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate (3.0 g, 6.98 mmol) was dissolved in THF (50 mL) and water (10 mL) and lithium hydroxide monohydrate (586 mg, 13.95 mmol) added. The resultant mixture was heated with stirring at 45° C. for 2 hours, then at ambient temperature for 16 hours, and at 45° C. for a further 4 hours. Water (40 mL) was added and the solvent removed in vacuo. The resultant solution was acidified carefully with 1M citric acid (2 equivalents), washed with water and brine then dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a colourless gum (2.58 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[NH:4][N:3]=1.CN(C=O)C.[Cl:16]N1C(=O)CCC1=O>O>[Cl:16][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cc1cc(C(F)(F)F)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c(C(F)(F)F)c1Cl
Temperature: 70 °C

Procedure:
3-methyl-5-trifluoromethylpyrazole was taken into dry DMF (20 mL) and N-chloro succinimide (1.78 g) was added in portions. The mixture was then heated at 70° C. for 22 h, cooled to room temperature, and then water (100 mL) was added and the mixture extracted with ethyl acetate (4×25 mL). The organic layer was washed with water and brine and dried with Na2SO4. Evaporation of the solvent afforded the title compound.