Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:5][C:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:8][CH:7]=1)([CH3:3])[CH3:2].I(C1C=CC=CC=1)=O.[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>ClCCl>[N:35]([CH:8]1[CH:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:10][CH2:11][C:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])=[CH:7]1)=[N+:36]=[N-:37]
Reactant: CC(C)[Si](OC1=CCC(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: O=Ic1ccccc1
Solvent: ClCCl
Product: CC(C)[Si](OC1=CC(N=[N+]=[N-])C(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a three-neck flask, a stirred solution of triisopropyl{[4-(2,4,5-trifluorophenyl)cyclohex-1-en-1-yl]oxy}silane (26.06 g, 0.068 mol) in dichloromethane (260 mL) was cooled to −15° C. and treated with iodosobenzene (19.5 g, 0.089 mol) in four portions followed by azidotrimethylsilane (24 mL, 0.116 mol) while maintaining the temperature below −10° C. Stirring was continued for 1.5 h. The reaction mixture was allowed to warm to room temperature briefly, then cooled again back to −15° C. and filtered. The filtrate was evaporated under vacuum below 25° C. to give the title compound which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH:25]N(C)C)[C:20](OCC)=[O:21])=[CH:15][CH:14]=1)#[N:12].Cl.CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([N:8]2[C:20]([OH:21])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=3)[CH:25]=[N:9]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Reactant: Cc1cc(NN)ncc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Combined 5-bromo-2-hydrazinyl-4-methylpyridine (6.0 g, 29.85 mmol) and isopropanol (100 mL) and added ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (8.02 g, 32.84 mmol) and HCl solution (aqueous, 1.85%, 49.75 mL) and stirred at room temperature for 2 h, then DIEA (19.40 g, 149.25 mmol) was added. After about 30 minutes the reaction was evaporated to give a residue which was extracted with EtOAc (50 mL×2) and water (50 mL×2), the EtOAc layers were combined and washed with brine, dried over Na2SO4 to give a residue which was purified by flash chromatography (petroleum ether:EtOAc 5:1-1:8) to give the title compound (8.67 g, 82.04%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][C:6](=[O:17])[CH:5]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=4)[NH:7][C:6](=[O:17])[CH:5]=3)[CH2:19][CH2:20]2)=[CH:25]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=c1cc(CCBr)c2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 50 °C
Reaction time: 30 h
Yield: 51.2 %

Procedure:
A suspension of 4-(2-bromoethyl)-6-nitro-2(1H)-quinolinone (II-9) (891 mg, 3.0 mmol), 3-(4-piperidinyl)-1H-indol (600 mg, 3.0 mmol) and sodium hydrogen carbonate (378 mg, 4.5 mmol) in dimethylformamide (9 ml) was stirred at 50 ° C. for 30 hours. Then the reaction mixture was poured into water. The precipitated solid was filtered, washed with water, dried and recrystallized from a mixed solvent consisting of methanol, tetrahydrofuran and water to give the desired compound (III-19) (640 mg, yield 51.2%) as pale yellow crystals, mp 251°-253 ° C. (recrystallized from a mixture of methanol, tetrahydrofuran and water).
Reaction SMILES: CC#N.[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][Si:30]([CH2:33][CH2:34][O:35][CH2:36]Cl)([CH3:32])[CH3:31]>C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1C(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
Dry CH3CN (50 mL) was added to 2-(4-hydroxybenzoyl)benzoic acid methyl ester (3.65 g, 15 mmol) followed by cesium carbonate (5.4 g, 16.5 mmol) and trimethylsilylethoxymethylchloride (2.9 mL, 16.5 mmol). The system was stirred at room temperature under nitrogen for 24 h and monitored by TLC. Removal of the solvent gave a light yellow oil that was taken up into ethyl acetate (100 mL), washed with water (3×50 mL), brine (40 mL) and dried with MgSO4. The solvent was removed and the crude product was purified by flash column chromatography (5:95 EtOAc:petrol) to give 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]benzoic acid methyl ester as a yellow oil (3.94 g, 10.2 mmol, 67%); Rf 0.79 (40:60 EtOAc:petrol). λmax (CH3OH)/nm 282, Abs 1.072. IR: 2939, 1720, 1666, 1589, 1489 cm−1. 1H NMR: (300 MHz, CDCl3) δ 0.00 (s, 9H, Si—(CH3)3), 0.94 (m, 2H, R—O—CH2—CH2—Si), 3.66 (s, 3H, COOCH3), 3.75 (m, 2H, O—CH2—CH2—Si), 5.27 (s, 2H, O—CH2—O), 7.05 (m, 2H, Ar—H), 7.37 (m, 1H, Ar—H), 7.53-7.66 (dtd, 2H, J=22.6, 7.4, 1.4 Hz, Ar—H), 7.72 (m, 2H, Ar—H), 8.05 (m, 1H, Ar—H). 13C NMR: (75 MHz, d6-DMSO) δ −2, 16.8, 51.5, 65.3, 91.5, 115.1, 127, 128, 129, 129.2, 129.6, 130.4, 132, 140.7, 160.2, 165.2, 194. LC/MS-ES+ m/z 163.2, 297.1, 387.1 [MH+], 409 [MNa+]. HRMS (EI) m/z Calcd. for C21H26O5Si: 386.1549. Found 386.1562.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])(=[O:11])[CH3:10].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([C:33](=[O:34])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (96.3 mL of a 2.0M solution, 0.193 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 3,7-dimethyl-1,6-octadien-3-yl acetate (17.81 g, 0.091 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 1-naphthoyl chloride (16.82 g, 0.086 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[CH:21][CH:20]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1NC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (85.9 mg, 0.30 mmol), 2-amino-benzoic acid methyl ester (0.07 mL, 0.54 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (103.5 mg, 0.54 mmol) and 1-hydroxybenzotriazole (HOBt) (73.0 mg, 0.54 mmol) in DMF (3.6 mL) was added N,N-diisopropylethylamine, redistill (DIPEA) (69.8 mg, 0.10 mL, 0.54 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeEOH=12:3:1) to give 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (46.4 mg, 3.69% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=O.OC(C(F)(F)F)=O.[NH2:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40].C[O-].[Na+]>CCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:6][C:5]=1[C:3]([NH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40])=[O:2]
Reactant: COC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 74.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-1-phenyl-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.13 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (125 mg, 0.54 mmol) and NaOMe (58 mg, 1.08 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 44 mg of the title compound as a yellow solid. MS: (+) m/z 457.26 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS(O[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:35])=[C:24]([C:26]3[O:27][C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)[CH:25]=2)[CH:17]=[N:16]1)(=O)=O>CN(C=O)C>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[C:24]1[C:23]([NH2:35])=[N:22][CH:21]=[C:20]([C:18]2[CH:17]=[N:16][N:15]([CH2:14][CH2:13][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:19]=2)[CH:25]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Solvent: CN(C)C=O
Product: CN1CCN(CCn2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 1-methylpiperazine (0.115 ml) was added to 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethyl methanesulphonate (138 mg) dissolved DMF (5 ml). The resulting solution was stirred at 100° C. for 1 hour. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 2 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and the solid was triturated with hot acetonitrile to afford 3-(1,3-benzoxazol-2-yl)-5-[1-[2-(4-methylpiperazin-1-yl)ethyl]pyrazol-4-yl]pyridin-2-amine (109 mg) as a solid. NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 2.30 (bs, 4H), 2.44 (bs, 4H), 2.74 (t, 2H), 4.23 (s, 2H), 7.40-7.50 (m, 2H), 7.65 (bs, 2H), 7.77-7.82 (m, 1H), 7.82-7.87 (m, 1H), 7.90 (s, 1H), 8.24 (s, 1H), 8.40 (d, 1H), 8.51 (d, 1H); Mass spectrum: M+H+ 404.
Reaction SMILES: [C:1]([CH2:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)(=[O:6])=[O:5])#[N:2].C1C=C([O:37]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[C:1]([CH2:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][NH+:25]([O-:37])[C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)(=[O:6])=[O:5])#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(=O)(=O)CC#N)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(=O)(=O)CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-N-[[3-[4-[4-[(cyanomethyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (VIII-G, R1=COCH3, R9=NCCH2, X1=F, X2=H) (0.550 g) is dissolved in 15 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.616 g) is added and the reaction is stirred at room temperature for 4 hours. The reaction is then filtered and the filtrate is concentrated to afford an oil. This oil is chromatographed on silica gel using 10% methanol (saturated with ammonia) in chloroform as eluent to afford 0.42 g of the N-oxide.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:18]([OH:26])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.[Cl-].[Na+].O>[CH2:27]([O:26][C:18]([C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:9][C:4]=1[Cl:3])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cn1cncn1)(OCc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reaction time: 18 h
Yield: 68.9 %

Procedure:
Sodium hydride (0.04 g) was added to a solution of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol (0.5 g) in THF (15 mL). After 30 min benzylbromide (0.27 g) was added and the mixture was stirred for 18 h at reflux. Brine was added and the mixture was extracted with dichloro methane (3×). The combined organic phases were dried, filtered through a silica plug and evaporated. The crude product was purified by column chromatography to yield 0.43 g of the desired compound.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: C=C(Cl)COc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=C(Cl)COc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
1 36 g of lithium aluminum hydride was suspended in 50 ml of diethyl ether, and a solution of 7.0 g of 4-(2-chloro-2-propeneoxy)benzonitrile in 40 ml of diethyl ether was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes and then 10 ml of water was added dropwise for 30 minutes. The insoluble matter was removed by filtration. The ether layer was dried and diethyl ether was evaporated under reduced pressure to give 6.7 g of the desired 4-(2-chloro-2-propeneoxy)benzylamine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:26][C:27]([F:32])([F:31])[CH2:28][CH2:29]I>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][CH2:28][C:27]([F:32])([F:31])[F:26]
Reactant: FC(F)(F)CCI
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCCC(F)(F)F)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and 1,1,1-trifluoro-3-iodopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2cccnc2c1OCc1ccccc1
Yield: 77 %

Procedure:
7-Methyloxy-8-hydroxyquinoline (1.10 g; 6.29 mmol) and K2CO3 (1.30 g; 9.43 mmol) in 30 ml of dry acetonitrile are stirred for 10 minutes under argon. Benzyl chloride (0.87 ml, 7.54 mmol) is then added and the reaction medium is heated under reflux overnight. After returning to ambient temperature, the precipitate is filtered, washed with CH2Cl2 and the filtrate is concentrated under reduced pressure. The oil obtained is dissolved again in CH2Cl2 (50 ml) and washed in succession with an aqueous solution of NaOH 2 N (4×50 ml) and water (1×50 ml). The organic phase is dried over anhydrous Na2SO4 and the solvent is evaporated under reduced pressure to yield 7-methyloxy-8-[(phenylmethyl)oxy]quinoline in the form of a brown oil (1.28 g; 4.84 mmol, yield=77%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.94 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.06 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.59-7.51 (m, 3 H); 7.36-7.24 (m, 5H); 5.40 (s, 2H); 3.92 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 151.3 (CH); 149.5 (Cq); 142.9 (Cq); 141.2 (Cq); 137.4 (Cq); 135.3 (CH); 127.9 (CH); 127.4 (CH); 127.1 (CH); 123.6 (Cq); 122.9 (CH); 118.5 (CH) 114.8 (CH); 75.2 (CH2); 56.1 (CH3). MS (CID, NH3): m/z=266 (MH+). Analysis (%) for C17H15NO2.0.05 CHCl3: calculated C, 75.49. H, 5.59. N, 5.16. found C, 75.74. H, 5.40. N, 5.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[C:33]([OH:46])=[C:34]([S:42](Cl)(=[O:44])=[O:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C(Cl)Cl>[Cl:31][C:32]1[C:33]([OH:46])=[C:34]([S:42]([N:15]([CH2:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:44])=[O:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=1
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cc(C(F)(F)F)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Yield: 57 %

Procedure:
1-(4′-Chlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (Compound A of Example 232, 200 mg, 0.6 mmol, 1.0 eq) was dissolved in dry DCM (20 mL) then stirred and cooled to 0° C. Triethylamine (186 mg, 1.86 mmol, 3.0 eq) was added slowly and the mixture was stirred for 30 minutes. 3-Chloro-2-hydroxy-5-(trifluoromethyl)benzene-1-sulfonyl chloride (180 mg 0.6 mmol 1.0 eq) dissolved in DCM was added to the above solution and the resulting mixture was stirred for 12 h at ambient temperature. The solution was concentrated under reduced pressure and the residue was purified by silica gel (240-280) column chromatography using 20-30% ethyl acetate/hexane as the eluent to afford the title compound (0.2 g, 56%). 1H NMR (400 MHz, CD3OD) δ 7.92 (d, 1H), 7.79 (d, 1H), 7.43 (d, 5H), 7.32-7.29 (t, 1H), 7.27-7.25 (m, 2H), 7.23 (s, 1H), 7.15-7.13 (d, 1H), 6.98-6.94 (t, 2H), 4.89 (s, 1H), 4.58-4.53 (d, 2H). MS (ESI): 585.8 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C(Cl)(Cl)Cl>[F:19][C:20]([F:27])([F:26])[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCc1cc(-c2cccs2)[nH]c1-c1cccs1
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1cc(-c2cccs2)[nH]c1-c1cccs1)C(F)(F)F
Reaction time: 8 h
Yield: 45 %

Procedure:
A solution containing 100 mg (0.36 mmol) of 3-(2-aminoethyl)-2,5-dithienylpyrrole (XXII), 2 mL of ethyl trifluoroacetate, and 5 mL of CHCl3 was allowed to stand at ambient temperature overnight. The CHCl3 solvent was removed in vacuo, and the product XXIII isolated by preparative SiO2 -TLV plates (20 ×20 ×1000u) eluted with a 9:1 toluene-dioxane solvent mixture. Sixty mg of compound XXIII was obtained (45% yield).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH2:23])[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[C:16]2[NH:17][C:18]([NH2:22])=[N:19][C:20](=[O:21])[C:15]=2[N:14]=[CH:13]1)=[O:6])[CH3:3].[CH:24]([O-])=[O:25].[NH4+]>CN1CCCC1=O>[CH3:3][CH:2]([C@H:4]([NH:23][CH:24]=[O:25])[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[C:16]2[NH:17][C:18]([NH2:22])=[N:19][C:20](=[O:21])[C:15]=2[N:14]=[CH:13]1)=[O:6])[CH3:1]
Reactant: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: CC(C)[C@H](NC=O)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 125 °C

Procedure:
A 100 ml round bottom flask equipped with magnetic stir bar is charged with 7.25 gr Valacyclovir (20 mmol), 1.97 gr ammonium formate (31.2 mmol), NMP (N-Methyl-pyrrolidone) (15 ml) is added and stirring is started. The resulting mixture is placed in an oil bath that is heated to 125° C. for 2 hrs. The mixture is removed from the oil bath, allowed to cool to room temperature, and the solvent is removed under reduced pressure using high vac. pump. The residue is crystallized from 150 ml boiling water to give 6.0 gr at the purity of 80%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[CH:6]1([Mg]Cl)[CH:10]=[CH:9][CH:8]=[CH:7]1>>[CH2:2]([C:10]1[CH2:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Cl[Mg]C1C=CC=C1
Product: CCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-bromobutane (105 g, 0.766 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 20 minutes. After stirring for an additional 2 hours at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (85 g, crude butylcyclopentadiene). To the crude butylcyclopentadiene (75 g) dissolved in methanol (500 mL) was added acetone (54 mL) followed by pyrrolidine (63 mL) at 0° C. The mixture was warmed up to room temperature and stirred for 24 hours. The reaction was quenched with a mixture of ice and acetic acid. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave the desired product (89 g) as a brown liquid.