Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3].C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26]>C1(C)C=CC=CC=1>[Br:23][CH:24]([CH3:28])[C:25]([O:15][C:2]([CH3:1])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3])=[O:26]
Reactant: CC(Br)C(=O)Br
Reactant: CCCCCCCCCCCC(C)(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(C)(C)OC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of 2-methyltridecan-2-ol 73 (5 g, 23.4 mmol) in Toluene (50 mL) was added triethylamine (3.29 mL, 23.4 mmol)) and followed by 2-bromopropionyl bromide 58 (5.11 g, 23.7 mmol) at 5-10° C. The reaction mixture was stirred for 3 hours at 55-60° C.; the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated, the organic layer was washed with brine, and the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 74 (5 g, yield: 61.27%) as a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20]>C(OCC)(=O)C.CCOCC>[CH3:15][C:14]([CH3:17])([OH:16])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:18]1[CH2:19][CH3:20]
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Reactant: CCOC(CC)(OCC)OCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Yield: 84.2 %

Procedure:
A mixture containing 15.4 g (0.067 mol) of 1-[(3-amino-4-quinolinyl)amino]-2-methyl-2-propanol (U.S. Pat. No. 4,689,338 example 189) and 14.5 mL (0.07 mol) of triethyl orthopropionate was heated at about 165° C. for about 2 hours. The resulting solid was slurried in a mixture of ethyl acetate and ether, collected and dried to provide 15.2 g of a solid. This material was used without further purification.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([N:16]([CH2:21][C:22](O)=O)[CH2:17][C:18](O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:18]1[CH2:17][N:16]([CH2:21][C:22]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Solvent: OCCO
Product: c1ccc(CN(Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc1

Procedure:
2d was synthesised by an analogous procedure to that described for 2a using o-phenylenediamine (2.41 g, 22.34 mmol) and benzyliminodiacetic acid (4.10 g, 11.17 mmol) in ethyleneglycol (10 ml) at 190° C. Yield 3.50 g (85%). 1H NMR (250.13 MHz, DMSO-d6, r.t.), δ 3.74 (s, 2H, CH2), 3.97 (s, 4H, NCH2), 7.19-7.58 (overlapping and broad m, 13H, ArH). 13C NMR (100.6 MHz, MeOH-d4, r.t.), δ 56.24 (NCH2), 62.34 (CH2), 102.03 (ArC), 126.94 (ArC), 132.37 (ArC), 133.38 (ArC), 134.23 (ArC), 142.70 (ArCq), 143.47 (ArCq), 157.41 (ArCq). +CI MS (m/z): 367 ([MH+]).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[K+].Cl>CS(C)=O.O.C(Cl)(Cl)Cl>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:13]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 g of 2,3,4-trifluoronitrobenzene was dissolved in 150 ml of dimethyl sulfoxide, and to this mixture a solution of 10% potassium hydroxide was added dropwise while keeping the temperature at 18° to 20° C. Then, the mixture was stirred for 2 hours at room temperature and one liter of water was added to this reaction mixture and the mixture was shaken with chloroform. The water layer was acidified with hydrochloric acid and was extracted with chloroform. The extract was washed with water and was dried, then chloroform layer was concentrated. The residue was purified by silica gel column chromatography to provide 5.8 g of 2,3-difluoro-6-nitrophenol as yellow oil.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2(O)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:6]1>CCO>[NH:16]1[CH2:17][CH2:18][CH:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)[CH2:15]1
Reactant: OC1(c2c[nH]c3ncccc23)CCCNC1
Solvent: CCO
Solvent: CC(=O)Cl
Product: C1=C(c2c[nH]c3ncccc23)CNCC1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
10 ml acetylchloride was slowly added to 200 ml of EtOH (−10° C.). After 15 minutes, this solution was added to compound 4 (5 g, 16.3 mmol) and heated to reflux for 1 hour. The mixture was cooled, concentrated and re-dissolved in MeOH. Filtration over 25 g SCX-2 (MeOH followed by 1 N NH3/MeOH) gave the title compound (1.43 g, 7.18 mmol, 44.1%) as amorphous material. 1H-NMR (400 MHz, CDCl3): δ 11.4-10.8 (bs, 1H), 8.32 (dd, J=5 Hz, 2 Hz, 1H), 8.2 (dd, J=8 Hz, 2 Hz, 1H), 7.15 (dd, J=8 Hz, J=5 Hz, 1H), 6.32-6.27 (m, 1H), 3.76-3.72 (m, 2H), 3.10-3.04 (m, 2H), 2.36-2.29 (m, 2H). (TLC MeOH/triethylamine (97/3 Rf 0.25).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:27]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([I:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-iodo-2′-deoxyuridine (5.0 g, 14 mmol) in 70 ml in dry N,N-dimethylformamide (DMF) was added imidazole (1.09 g, 16 mmol), followed by (2.41 g, 16 mmol) TBDMSCl at 0° C. The mixture was left in the ice bath and stirred overnight. The reaction was quenched with sat. aq. NaCl solution and extracted with EtOAc. After drying (MgSO4), the solvent was removed and the crude mixture was purified by chromatography on silica (EtOAc:petroleum ether 3:7). The product (33) (5.9 g, 90%) was obtained as a colourless solid. 1H NMR (d6 DMSO) δ 0.00 (s, 3H, CH3), 0.79 (s, 9H, tBu), 1.88-1.97 (m, 1H, H-2′), 2.00-2.05 (m, 1H, H-2′), 3.59-3.71 (m, 2H, H-5′), 3.75 (br s, 1H, H-4′), 4.06 (br s, 1H, H-3′), 5.18 (d, J=4.0 Hz, 1H, OH), 5.98 (t, J=5.9 Hz, 1H, H-1′), 7.89 (s, 1H, H-6), 11.62 (s, 1H, NH). Mass (−ve electrospray) calcd for C15H25IN2O5Si, 468.06. found 467.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82](O)[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:85]=[C:84]([CH:83]=[CH:82][CH:81]=2)[O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[N:60][CH:59]=[N:58]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C1CCCN1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCN1CCOc1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.9 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 1-(2-hydroxyethyl)pyrrolidin-2-one (0.299 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6N hydrochloric acid (25 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6N sodium hydroxide (25 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate followed by 0–15% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.0768 g, 30% yield). 1H NMR (CD3OD) δ 13.41 (br s, 1H), 8.65 (s, 1H), 8.10 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 7.50 (m, 2H), 7.05 (m, 1H), 4.20 (t, 2H), 3.60 (t, 2H), 3.50 (t, 2H), 2.25 (t, 2H), 1.95 (m, 2H). ES-MS (m/z) 389 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Br
Product: CC(Nc1cc(Cl)cc(Cl)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 76.5 %

Procedure:
3,5-dichloroaniline (132 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3,5-dichlorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (75 mg, 75%) as a white solid. Mass Spectrum: M+H+ 490. NMR Spectrum (DMSOd6): 1.52 (d, 3H), 2.75 (bs, 3H), 2.95 (bs, 3H), 3.51-3.63 (m, 4H), 3.70-3.78 (m, 4H), 5.01-5.09 (m, 1H), 5.61 (s, 1H), 6.50 (s, 2H), 6.61 (s, 1H), 6.91 (d, 1H), 7.54 (d, 1H), 7.81 (d, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[K+].[N+:13]([CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])#[C-:14]>CO>[CH3:1][O:2][C:3]1[C:8]([C@@H:9]2[O:10][CH:14]=[N:13][C@H:15]2[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1C=O
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ncccc1[C@@H]1OC=N[C@H]1C(=O)N1CCCC1
Yield: 50 %

Procedure:
BAL 01014 was prepared in accordance with method D using 2-methoxy-3-pyridinecarboxaldehyde (0.64 ml, 5.43 mmol), KOH (0.305 mg, 5.43 mmol) in methanol (5 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up trans-(4,5-dihydro-5-(2-methoxypyridin-3-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone BAL 01014 was obtained (0.74 mg, 50% yield) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH:10]([C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[NH2:11]>CO.C(O)(=O)C>[NH:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:10][N:11]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: NNc1nc2ccccc2[nH]1
Reactant: CC(=O)c1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2[nH]1)c1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl pyridine (1.00 g, 8.25 mmol) and 2-hydrazinobenzimidazole (1.22 g, 8.25 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored in the refrigerator at approximately 5° C. for 24 hours. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether. Yield: 1.45 g (70% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:13])([CH3:12])[CH2:9][C:10]#[N:11].B.O1CCCC1.[ClH:20]>O1CCCC1>[ClH:20].[NH2:11][CH2:10][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([OH:13])[CH3:12]
Reactant: CC(O)(CC#N)c1ccccc1F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)(CCN)c1ccccc1F
Temperature: 75 °C
Yield: 92.9 %

Procedure:
To a stirring solution of 3-(2-fluoro-phenyl)-3-hydroxy-butyronitrile (878 mg, 4.9 mmol) in tetrahydrofuran (5 mL) was slowly added a solution of borane-tetrahydrofuran complex (12.8 mL, 12.8 mmol, 1M in tetrahydrofuran). After bubbling ceased, the reaction mixture was heated to 75° C. for 2 hours and then allowed to cool to ambient temperature and concentrated. Methanol (5 mL) was added dropwise followed by hydrogen chloride (5.4 mL, 23.8 mmol, 4N in 1,4-dioxane). The resulting mixture was heated to reflux for 2 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. The residue was triturated with ether and the precipitate was filtered, washed with ethyl acetate and air dried to give the product as a white solid (1 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=2[Cl:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br.CO.O>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Cl:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(Oc2ccc(C#N)c(Cl)c2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N#Cc1ccc(Oc2ccc(O)cc2Cl)cc1Cl

Procedure:
0.5 g (1.7 mmol) of 2-chloro-4-(2-chloro-4-methoxy-phenoxy)-benzonitrile and 2.21 mL (2.21 mmol) of boron tribromide 1M in dichloromethane were stirred in 5.5 mL dichloromethane for 5 days at RT. The mixture was carefully combined with methanol and then water and dichloromethane were added. The phases were separated and the aqueous phase was extracted twice more with dichloromethane. The organic phase was dried on sodium sulphate and evaporated down.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][CH3:14].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][N:10]=[C:11]2[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)NCCc1ccccc1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: CCCC1=NCCc2c(C)cccc21
Temperature: 140 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
N-[2-(2-methylphenyl)ethyl]butanamide (4.58 g) was dissolved in xylene (30 mL), and then diphosphorus pentoxide (10 g) was added thereto, followed by stirring at 140° C. for 4 hours. The reaction mixture was left to cool and then the solvent was evaporated. An aqueous 8 M potassium hydroxide solution, water, and chloroform were used to dissolve completely the insoluble materials. The reaction mixture was adjusted to a pH of around 8, and extracted with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 5-methyl-1-propyl-3,4-dihydroisoquinoline (2.14 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CC2)c1

Procedure:
Alkylation reaction of phenol 58 with cyclopropylmethylbromide gave 2-(3-(3-(cyclopropylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.410 g, 36%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.73-6.78 (m, 2H), 6.67 (dd, J=8.0, 2.4 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=7.6, 2.4 Hz, 1H), 4.52 (s, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.72-3.78 (m, 4H), 2.65 (t, J=7.6 Hz, 2H), 1.98-2.07 (m, 2H), 1.24-1.28 (m, 1H), 0.62-0.66 (m, 2H), 0.32-0.36 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 37 °C

Procedure:
To a 2-liter, 3-necked, round-bottom flask is added 680 ml of concentrated H2SO4 and 400 g of p-chlorobenzoic acid. The mixture is stirred and brought to 0° C. by means of a constant temperature bath. A solution of concentrated HNO3 (216 ml) and concentrated H2SO4 (216 ml) is added dropwise to the reaction mixture at such a rate as to maintain the temperature between 10° C. and 25° C. Upon completion of the addition, the reaction temperature is raised to 37° C. and the mixture is allowed to stir for a period of 10-14 hours. The reaction mixture is then poured over crushed ice and the product, 4-chloro-3-nitrobenzoic acid, is filtered and dried, having a yield of 525.7 g or 98.7 percent with a melting point of 178° C.-180° C. This material is used without further purification.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]([CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[C@@H:12]([CH3:24])[NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=CC=1)([O-])=O.[H-].C([Al+]CC(C)C)C(C)C.CO.[OH-].[Na+]>C(Cl)Cl>[OH:10][C@H:11]([CH2:25][O:26][Si:27]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:34]([CH3:35])[CH3:36])[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:24]
Reactant: CC(C)[Si](OC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)[Si](OC[C@@H](O)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Temperature: -40 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
(5R,6S)-5,10-Dimethyl-3-oxo-1-phenyl-9,9-di(propan-2-yl)-2,8-dioxa-4-aza-9-silaundecan-6-yl 4-nitrobenzoate (7.90 g, 14.5 mmol) synthesized in Example (89c) was dissolved in methylene chloride (150 mL), and diisobutylaluminum hydride (1.0 mol/L hexane solution, 30.0 mL, 30.0 mmol) was added, followed by stirring at −40° C. for 8 hours under nitrogen atmosphere. The reaction solution was brought back to 0° C., and methanol (5.0 mL) was added, followed by addition of a 5N aqueous sodium hydroxide solution (150 mL), and extraction was carried out with methylene chloride (200 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-15%) to afford the desired compound (3.70 g, yield 65%) as a colorless liquid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].[Cl:14][C:15]1[CH:16]=[C:17](OS(C(F)(F)F)(=O)=O)[CH:18]=[N:19][CH:20]=1>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17]([C:13]#[C:12][Si:9]([CH3:11])([CH3:10])[CH3:8])[CH:16]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(Cl)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
Sequentially add triethylamine (16 mL, 114 mmol), trimethylsilyl acetylene (4.5 mL, 34.1 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.538 g, 0.77 mmol), and copper (I) iodide (270 mg, 1.42 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester (7.4 g, 28.4 mmol), (prepared as described in PREPARATION 25), in ethyl acetate (25 mL) under nitrogen. Heat at 60° C. for 1 h, cool to room temperature, stir for 12 h, filter through diatomaceous earth and wash with diethyl ether. Concentrate and purify the residue by silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes, to give the title compound as an orange oil (5.51 g, 92%).
Reaction SMILES: [Mg].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[N:11]([CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[C:24]([O-:26])=[O:25])=[CH:18][CH:17]=1)[CH3:12].II.[CH3:37]O>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[N:11]([CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([O:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[C:24]([O:26][CH3:37])=[O:25])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CO
Reactant: CN(CCOc1ccc(CC(Oc2ccc(Cl)cc2)C(=O)[O-])cc1)c1nc2ccccc2o1
Agent: II
Agent: [Mg]
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Oc1ccc(Cl)cc1

Procedure:
Magnesium turnings (0.5 g) were added to a mixture of methyl (E/Z) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(4-chlorophenoxy)propanoate (0.98 g) and a crystal of iodine dissolved in methanol (50 mL) at room temperature. The mixture was warmed gently with a heat gum until reaction ensued, at which pint the heating was stopped and the mixture stirred at room temperature during the addition, over ca 5 minutes, of a further portion of magnesium (2.00 g). The reaction mixture was immersed in a cold water bath and stirring continued until all the metal had dissolved (~4 hrs), then the mixture was evaporated in vacuo. The residue was suspended in water (100 mL) and stirred vigorously during the addition of concentrated hydrochloric acid, to give (once all the suspension had dissolved) a final pH of 1.5. The mixture was extracted with ethyl acetate (2×100 mL) and the combined ethyl acetate layers then washed with water (500 mL), brine (300 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with 3% ethyl acetate in dichloromethane as eluent to afford the title compound, mp 88°-90° C.
Reaction SMILES: O1CCC[CH2:2]1.[Cl:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]([F:15])=[C:9]([Cl:16])[N:8]=1.[H-].[Na+].COCCl>C(OCC)(=O)C.O>[Cl:16][C:9]1[C:10]([F:15])=[CH:11][C:12]([CH2:13][O:14][CH3:2])=[C:7]([Cl:6])[N:8]=1
Reactant: C1CCOC1
Reactant: OCc1cc(F)c(Cl)nc1Cl
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 100 mL of a tetrahydrofuran solution containing 5.8 g of (2,6-dichloro-5-fluoropyridin-3-yl)methanol, 1.8 g of 60% sodium hydride and 2 mL of a tetrahydrofuran solution containing 2.4 mL of chloromethyl methyl ether were added under cooling with ice, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added thereto, the organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 5.6 g of a colorless oily substance, 2,6-dichloro-3-fluoro-5-((methoxy)methyl)pyridine.