Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[O:14]([CH2:13][C:10]1[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: Brc1ccc(COc2ccccc2)nc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(COc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
To a diethyl ether (250 mL) solution of 5-bromo-2-phenoxymethyl-pyridine (4.40 g, 16.6 mmol) described in Manufacturing Example 54-1-3 was added n-butyl lithium (2.55 M n-hexane solution, 8.46 mL, 21.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 40 minutes at −78° C. N,N-dimethylformamide (1.93 mL, 25.0 mmol) was then added dropwise thereto and stirred for 20 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (1.00 g, 28.3%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:14][CH:15](O)[C:16]#[CH:17].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[I:14][CH:15]([O:12][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]#[CH:17]
Reactant: C#CC(O)I
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CC(I)OC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a magnetically stirred solution of N-t-butoxycarbonyl-L-alanine (5.00 g., 0.026 mole) and iodopropargyl alcohol (4.81 g., 0.026 mole) in anhydrous dichloromethane (100 ml.) cooled to 0° C. with an ice-bath was added 4-dimethylaminopyridine (0.32 g., 0.0026 mole) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.57 g., 0.029 mole). The reaction mixture continued to stir at 0° C. for one hour, and was then stored in a refrigerator at 5° C. overnight. The reaction mixture was transferred to a separatory funnel and diluted to double volume (200 ml.) with dichloromethane, then washed successively with 100 ml. of water, 3×100 ml. of 10% aqueous potassium hydrogen sulfate, 100 ml. of water, 3×100 ml. of saturated aqueous sodium bicarbonate, 3×100 ml. of water and a final wash with 100 ml. of saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo with a rotary evaporator to a clear colorless oil which crystallized on standing. A quantitative yield (9.34 g.) of N-t-butoxycarbonyl-L-alanine iodopropargyl ester was obtained. m.p.=71°-73° C. 1H-NMR (200 MHz, DMSOd6) δ=1.25 ppm, d, 3H; 1.40, s, 9H; 4.01, m, 1H; 4.85, s, 2H; 7.33, d, 1H. IR (CHCl3) 1170, 1375, 1400, 1715, 1750, 2205 cm-1.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:13]=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][S:18][C:14]2[CH:13]=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: N#Cc1ccc(CCSc2cccc(N)c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CCSc2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Reaction time: 3 h
Yield: 82.1 %

Procedure:
Benzenesulfonyl chloride (0.62 g; 3.5 mmol) was added to a cold solution (ice:water temperature) of amino-3-[2-(4-cyanophenyl)ethylthio]benzene (0.80 g; 3.15 mmol; from step (ii) above) in a mixture of pyridine (1 mL) and CH2Cl2 (20 mL) over 10 minutes. After 3 hours stirring, 2M aqueous HCl was added and the solution extracted with CH2Cl2. The organic layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; Et2O:hexane (1:1)) to give 1.02 g (82%) of the sub-title compound.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:20](N)([CH3:22])[CH3:21]>C1CCCCC1>[CH:20]([NH:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:22])[CH3:21]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC(C)N
Solvent: C1CCCCC1
Product: CC(C)Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 93.5 %

Procedure:
63.3 g of 1-nitroanthraquinone (99% pure) in 320 ml of cyclohexane are reacted with 147.8 g of isopropylamine (molar ratio 10:1) for 70 minutes at a temperature of 160° C. and under a pressure of 50 bars. Working up analogously to Example 1 gives 62 g (94.5% of theory) of 97.6% pure 1-isopropylamino-anthraquinone.
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>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.C1(C)C=CC=CC=1>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(B(O)O)cc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(Br)cc1
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: [K+]
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(-c2ccc(OC)cc2)cc1
Yield: 60 %

Procedure:
At first, a mixture of the 4-(diallylethoxysilyl)bromobenzene (191 mg, 0.61 mmol) obtained in Example 1, Pd(PPh3)4 (21.3 mg, 0.018 mmol), K2CO3 (127 mg, 0.92 mmol), and 4-methoxyphenyl boronic acid (112 mg, 0.74 mmol) was added with dist.toluene (5 mL). Subsequently, the resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 13 hours to obtain a reaction mixture. Thereafter, a salt formed in the reaction mixture was removed by filtering with celite. The solvent was distilled from the organic layer with an evaporator to obtain a crude product. After that, the crude product thus obtained was separated and purified with PTLC (hexane/EtOAc=10/1), and thereby 4-(diallylethoxysilyl)-4′-methoxybiphenyl was obtained (125.4 mg, 60% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:5]([NH:13]C(=O)C(F)(F)F)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[OH-].[Na+]>O1CCOCC1.CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:5]([NH2:13])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: O=C(Nc1c(C2CCCO2)cc(Br)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: Nc1c(C2CCCO2)cc(Br)cc1[N+](=O)[O-]
Yield: 101.3 %

Procedure:
N-(4-bromo-2-nitro-6-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide (6) (54.00 g, 140.9 mmol) was dissolved in 1,4-dioxane (162 mL) and added aqueous 6 M NaOH (70.45 mL, 422.7 mmol, JT-Baker 567202). The reaction mixture was stirred at reflux for 2 days (HPLC showed complete conversion). The mixture was allowed to cool, diluted with MTBE (800 mL), and washed with water (2×200 mL), saturated aqueous NH4Cl, water, and brine. The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure to give (6a) as a dark amber oil (40.96 g, 93% yield; overall 92% HPLC plus NMR purity). LCMS (C18 column eluting with 10-90% MeOH/water gradient from 3-5 minutes with formic acid modifier) M+1: 287.28 (3.44 min). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 6.91 (s, 2H), 4.80 (t, J=7.2 Hz, 1H), 4.14-4.05 (m, 1H), 3.98-3.90 (m, 1H), 2.36-2.19 (m, 1H), 2.15-2.01 (m, 3H) ppm.
Reaction SMILES: [NH:1]1[CH:5]([C:6](O)=O)[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][C:11]1[CH:16]=C[CH:14]=[CH:13][C:12]=1[O:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>C(Cl)Cl.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:6]([CH:5]2[NH:1][C:2](=[O:9])[CH2:3][CH2:4]2)=[CH:10][C:11]=1[CH3:16]
Reactant: COc1ccccc1C
Reactant: O=C1CCC(C(=O)O)N1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CCC(=O)N2)cc1C
Temperature: 100 °C
Yield: 55.9 %

Procedure:
2-Pyrrolidone-5-carboxylic acid (2.0 g, 15.5 mmol) and 2-methylanisole (2.1 mL, 17.0 mmol) were added to a mixture of 1.0 g (3.52 mmol) of phosphorous pentoxide and 6.7 mL methanesulfonic acid. The mixture was heated at 100° C. for 2 hr, cooled down to rt, and poured into a mixture of H2O and CH2Cl2. The aqueous layer was separated, and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, washed with sat'd NaHCO3, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 4:1 v/v EtOAc/hexanes as the eluant afforded 1.78 g (56%) of the title compound: 1H NMR δ 1.88-1.97 (m, 1H), 2.21 (s, 3H), 2.35-2.54 (m, 3H), 3.81 (s, 3H), 4.66 (t, J=7.1, 1H), 6.53 (br. s, 1H), 6.79 (d, J=8.6, 1H), 7.05-7.09 (m, 2H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN1CCCC1=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[CH:15][CH2:14][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:18][CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC=Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 96 h
Yield: 87.1 %

Procedure:
18.5 g (0.11 mol) of N-hydroxyphthalimide and 31.4 g (0.11 mol) of 1-bromo-[3-(4-bromophenyl)]-prop-2-ene were added in succession to 350 ml of dry N-methylpyrrolidone, and 12.1 g (0.12 mol) of triethylamine were then added dropwise at room temperature. After stirring had been carried out for four days at 20° C., the reaction mixture was poured onto 1.5 1 of ice water and the solid was filtered off and washed with water and isopropanol. 34.3 g (86.8% of theory) of N-[3-(4-bromophenyl)-prop-2-enyloxy]-phthalimide with a melting point of 161°-162° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH3:9][N:10]=[C:11]=[S:12]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:11]([NH:10][CH3:9])=[S:12])=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: Nc1ccc(Cl)nc1
Solvent: CC#N
Product: CNC(=S)Nc1ccc(Cl)nc1
Yield: 70.6 %

Procedure:
A mixture of 4.07g of 2-chloro-5-aminopyridine, 2.55g of methyl isothiocyanate and 30ml of acetonitrile was refluxed for 13.5 hours, to which 0.70g of additional methyl isothiocyanate was added and the mixture was refluxed for 3.5 hours. The reaction mixture was concentrated, and the residue was purified by a column chromatography [developing solvent: dichloromethaneethyl acetate (1: 1)] to afford 4.51g of 1-(6-chloro-3-pyridyl)-3-methylthiourea.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.C(N(CC)CC)C.Cl>O1CCCC1>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: NCC1CCOCC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrofuran (30 mL) were stirred overnight, neutralized with concentrated HCl and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide the title compound.
Reaction SMILES: [CH2:1]([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:28][OH:29].N1C=CC=CC=1>O>[CH2:1]([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[O:22])[N:28]([OH:29])[C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500-ml flask equipped with a stirrer, a thermometer and a dropping funnel, 100 g (277.43 mmol) of 4-dodecyloxycarbonylphthalic anhydride, 21.21 g (305.17 mmol) of hydroxylamine hydrochloride and 250 g of pyridine were placed and were stirred at room temperature in an atmosphere of nitrogen gas for 30 minutes, followed by stirring at 90° C. for further 3 hours. The resulting reaction mixture was added dropwise to 3000 g of pure water over 30 minutes with stirring and thereby yielded a crystal of 4-dodecyloxycarbonyl-N-hydroxyphthalimide. The mixture was stirred for further 1 hour, the precipitate was separated by filtration and was rinsed with pure water. The resulting solid was stirred and rinsed in a solvent mixture of 640 g of n-hexane and 160 g of ethyl acetate for 3 hours, the resulting slurry was filtrated, was rinsed with n-hexane, was dried at 60° C. under reduced pressure and thereby yielded 90.88 g (242.04 mmol) of target 4-dodecyloxycarbonyl-N-hydroxyphthalimide as a white powder. The yield was 87.2% on the basis of 4-dodecyloxycarbonylphthalic anhydride.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:12][CH3:13])=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[F:11][C:8]1[C:5]([C:6]#[N:7])=[C:4]([O:12][CH3:13])[C:3]([CH:1]2[CH2:2][O:22]2)=[CH:10][CH:9]=1
Reactant: C=Cc1ccc(F)c(C#N)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(C2CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Ethenyl-6-fluoro-2-methoxybenzonitrile (1.67 g, 9.43 mmol) was added to DCM (50 mL) at 0° C. then mCPBA (4.88 g, 28.3 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was washed with saturated aqueous Na2S2O3, then with 1N NaOH followed by brine. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by chromatography through a 120 g Redi-sep column and eluting with a 0-100% EtOAc/hexane solvent system. Isolated 6-fluoro-2-methoxy-3-(oxiran-2-yl)benzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([F:23])=[CH:21][CH:22]=1)[CH2:5][C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:8].[CH3:24][Si:25]([CH3:68])([CH3:67])[CH2:26][CH2:27][O:28][C:29](=[O:66])[C@H:30]([CH2:42][C:43]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[CH:45][C:44]=1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.ClCCl>[CH2:59]([O:58][C:44]1[CH:45]=[CH:46][C:47]([C:2]2[CH:22]=[CH:21][C:20]([F:23])=[C:4]([CH2:5][C@H:6]([N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:8])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=2)=[CH:48][C:43]=1[CH2:42][C@H:30]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:29](=[O:66])[O:28][CH2:27][CH2:26][Si:25]([CH3:68])([CH3:67])[CH3:24])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)OC1(C)C
Reactant: COC(=O)[C@H](Cc1cc(Br)ccc1F)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)ccc1F)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.68 g (4.09 mmol) of methyl 3-bromo-N-(tert-butoxycarbonyl)-6-fluoro-N-methyl-L-phenylalaninate (Example 14O) in 8 ml of 1-methyl-2-pyrrolidone is rendered inert and saturated with argon (pass argon through for about 30 min). Then 334 mg (0.41 mmol) of bis(diphenylphosphino)ferrocenepalladium(II)chloride (PdCI2(dppf)) are added, and the mixture is stirred at RT for 10 min. Thereafter, 3.45 g (4.92 mmol) of 2-(trimethylsilyl)ethyl-2-(benzyloxy)-N-[(benzyloxy)carbonyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-L-phenylalaninate (Example 16A) in 8 ml of 1-methyl-2-pyrrolidone and 2.67 g (8.19 mmol) of cesium carbonate are added. A gentle stream of argon is passed over the reaction mixture, which is stirred at 50° C. for 20 h. The mixture is cooled, taken up in dichloromethane and washed with water. The organic phase is dried over magnesium sulfate, and the solvent is concentrated in vacuo. The residue is purified by column chromatography on silica gel (cyclohexane:ethyl acetate 7:3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(C)C=CC=C(N2[CH:19]=[N:18][C:17]([C:20]([OH:22])=[O:21])=[N:16]2)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH:19]=[N:18][C:17]([C:20]([OH:22])=[O:21])=[N:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(-n2cnc(C(=O)O)n2)c1
Reactant: Nc1cccc(Br)c1
Product: O=C(O)c1ncn(-c2cccc(Br)c2)n1

Procedure:
This intermediate was prepared from 3-bromoaniline in three steps according to the preparation of 1-m-tolyl-1H-[1,2,4]-triazole-3-carboxylic acid (Method B).
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)[NH2:2].Cl.[N:15]([O-])=O.[Na+]>C(OCC)C.O>[N:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)=[N+:2]=[N-:15]
Reactant: CCOC(=O)c1sc(NN)nc1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
To a cooled (0° C.) suspension of ethyl 2-hydrazinyl-4-methylthiazole-5-carboxylate (3.00 g, 14.92 mmol) in a mixture of diethyl ether (15 mL) and water (15 mL) was added hydrochloric acid (2.72 mL) dropwise. The reaction mixture was stirred for 10 minutes, and a solution of sodium nitrite (1.21 g, 17.46 mmol) in water (2 mL) was added. The mixture was stirred for 2 hours at 0° C. and extracted with diethyl ether. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:4) to afford the title compound as a yellowish solid (1.49 g, 47%): 1H NMR (300 MHz, CDCl3) δ 4.29 (q, J=6.0 Hz, 2H), 2.62 (s, 3H), 1.33 (t, J=6.0 Hz, 3H); MS (ES+) m/z 213.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[CH3:23].[OH-].[Na+]>COCCOCCOC>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH3:16])[CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: COc1cc2nccc(Oc3ccc(C)c(C)c3)c2cc1OC
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 3,4-dimethylphenol (274 mg) were suspended in diethylene glycol dimethyl ether (0.1 ml), and the suspension was stirred at 180° C. for 1.5 hr. The reaction solution was cooled to room temperature, an aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give 6,7-dimethoxy-4-(3,4-dimethylphenoxy)quinoline (160 mg, yield 58%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2cnccc2c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of isoquinoline (1-Im-9, 5 g, 1.0 eq) in 50 mL of CHCl3, mCPBA (2.0 eq) was added. The mixture was stirred at rt for 1 h. The reaction was washed with 5% aqueous Na2SO3 and aqueous Na2CO3, then concentrated and the residue was purified by silica column chromatography to give isoquinoline 2-oxide (2-Im-9).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18]O)=[CH:12][CH:11]=1)([O-:3])=[O:2].C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[F:26][CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccncc1-c1ccc(CCCO)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccncc1-c1ccc(CCCF)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To 3-(4-(4-nitropyridin-3-yl)phenyl)propan-1-ol (60 mg, 0.23 mmol) in 2 mL of dry DCM at 0° C. was added (Diethylamino)sulfur trifluoride (111 mg, 0.69 mmol) dropwise. The reaction was warmed to rt and stirred for 1 h and quenched onto ice (20 g) in saturated Na2CO3 (20 mL). The mixture was extracted with EtOAc (2×30 mL) and the organic phase was dried over MgSO4 and concentrated. The residue was purified by silica chromatography (EtOAc in hexane, 5% to 30%) to afford 3-(4-(3-fluoropropyl)phenyl)-4-nitropyridine as a pale-yellow oil (12 mg, 20%). 1H NMR (400 MHz, CDCl3): δ 8.82-8.80 (m, 2H), 7.64 (d, J=5.2, 1H), 7.33-7.27 (m, 2H), 4.55 (t, J=5.6 Hz, 1H), 4.43 (t, J=5.6 Hz, 1H), 2.82 (t, J=7.6 Hz, 2H), 2.12-1.99 (m, 2H); MS (ESI) m/z [M+H]+261.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([I:24])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[C:30]1([CH:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([I:24])=[N:18][C:19]=3[NH:38][CH2:37][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:7][C@@H:6]1[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
A mixture of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-iodo-9H-purin-9-yl)tetrahydro-3-furanyl acetate (J. Med. Chem., 35, 248, (1992)) (15.2g, 28.2 mmol), 2,2-diphenylethylamine (6.1 g, 30.9 mmol), triethylamine (11.4 g, 112.8 mmol) and acetonitrile (200 ml) was stirred at room temperature, under a nitrogen atmosphere, for 24 hours, followed by heating under reflux for 90 minutes. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (500 ml) and water (200 ml). The organic phase was separated and the solvent removed under reduced pressure to give the title compound as a pale yellow foam (18.8g).