Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:17]([CH:18]=O)=[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[O:9][C:5]2=[C:4]([O:20][CH3:21])[CH:3]=1.[NH2:22][OH:23].Cl>CCO.N1C(=O)CC[C@H]1C(O)=O>[OH:1][C:2]1[C:17]([CH:18]=[N:22][OH:23])=[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[O:9][C:5]2=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(O)c(C=O)c2cc(-c3ccc(O)cc3)oc12
Reactant: NO
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCO
Product: COc1cc(O)c(C=NO)c2cc(-c3ccc(O)cc3)oc12

Procedure:
Compound 71 (0.029 g, 0.1 mmol) in EtOH/Pyr (1 mL/0.5 mL) was treated with NH2OH HCl (0.040 g, 0.58 mmol) and the mixture heated briefly to reflux (approximately 5 minutes) and allowed to cool and then the solution was partitioned between EtOAc and 2 N HCl aq and the organic layer was then washed with NaHCO3 aq, brine, dried over MgSO4, filtered, concentrated and triturated with CH2Cl2 to render 29 mg of the desired oxime: Mp=205° C. (dec.); 1H NMR (DMSO-d6) δ 11.1 (s, 1 H), 10.0 (s, 1 H), 9.90 (s, 1H), 8.53 (s, 1 H), 7.65 (d, 2 H, J=8.6 Hz), 7.39 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.47 (s, 1 H), 3.94 (s, 3 H); MS 300 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: Fc1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (325 mg, 2.37 mmol) from Step 2 of this Example in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 100 mg, 2.49 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (600 mg, 2.61 mmol) from Step 4 of Example 36 in DMF (2 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (250 mL) and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (356 mg, 45%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.41 (t, J=2.0 Hz, 1H), 8.10 (dd, J=2.6, 9.4 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.3, 8.3 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C@H:25]([CH3:41])[C@@H:26]([O:32][C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[C@@H:27]([CH3:31])[CH2:28][CH:29]=[CH2:30])[C:3]([CH3:24])([CH3:23])[C@@H:4]([OH:22])[C@H:5]([CH3:21])[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7].N1C=CN=C1.[CH2:47]([Si:49](Cl)([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:48].O>CN(C)C=O>[O:1]=[C:2]([C@H:25]([CH3:41])[C@@H:26]([O:32][C:33]([O:35][CH2:36][C:37]([Cl:39])([Cl:40])[Cl:38])=[O:34])[C@@H:27]([CH3:31])[CH2:28][CH:29]=[CH2:30])[C:3]([CH3:23])([CH3:24])[C@@H:4]([O:22][Si:49]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:47][CH3:48])[C@H:5]([CH3:21])[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
A solution of (4S)-3-[(2S,3S,6R,7S,8S)-5-oxo-3-hydroxy-2,4,4,6,8-pentamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoyl]-4-benzyloxazolidinone (2.6 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: Cl.[C:2]([NH:6][C:7](=[O:14])[C@@H:8]1[CH2:12][C@H:11]([Cl:13])[CH2:10][NH:9]1)([CH3:5])([CH3:4])[CH3:3].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:35]([OH:39])[C:36](O)=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C@H:35]([OH:39])[C:36]([N:9]1[CH2:10][C@@H:11]([Cl:13])[CH2:12][C@H:8]1[C:7]([NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:14])=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
680 mg (2.23 mmol) of (4S)-1-t-butoxycarbonyl-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Preparation 2) were treated with 10 ml of a 4N solution of hydrogen chloride in dioxane, in order to eliminate the t-butoxycarbonyl group and give (4S)-N-t-butyl-4-chloro-L-prolinamide hydrochloride. The whole of the hydrochloride thus obtained and 880 mg (1.99 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) were dissolved in 5 ml of dimethylformamide, and the solution was cooled with ice. 420 mg (2.58 mmol) of diethyl cyanophosphate, followed by 640 mg (6.40 mmol) of triethylamine, were then added to the ice-cooled mixture, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with a 10% w/v aqueous solution of citric acid and then extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 850 mg of the title compound as a colorless powder, melting at 107°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9]([Cl:19])[CH2:10][C:4]=2[CH:3]=1
Reactant: OC1Cc2cc(Cl)ccc2Sc2ccc(F)cc21
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)C(Cl)Cc1cc(Cl)ccc1S2

Procedure:
58.3 G. of 2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol 300 ml. of benzene and 21 g. of finely pulverized calcium chloride are saturated with hydrochloric acid over a period of 2 hours at 15°. The resulting precpitate is filtered, washed with benzene and evaporated under reduced pressure, whereby there is obtained 2,10-dichloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin as white crystals, having a melting point of 84°-85°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[Cl:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Br:11])[C:3]=1[Cl:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccc(Br)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(Cl)c1CBr
Temperature: 0 °C
Yield: 97.2 %

Procedure:
Treat a mixture of 1-bromo-2,4-dichloro-3-methyl-benzene (76.01 g, 0.316 mol) and N-bromosuccinimide (59.2 g, 0.332 mol) in CCl4 (500 mL) with benzoyl peroxide (0.77 g, 3.18 mmol) and is heat to reflux for 6 hours under N2. Cool the reaction mixture to 0° C. and filter using hexanes to rinse the solids. Extract the filtrate with water and saturated NaHCO3. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford 97.89 g (97%) of the titled product. Rf=0.34 (100% hexanes).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:6][CH2:5][C:4](=[O:19])[NH:3]1.[H-].[Na+].Cl[CH:23]([OH:25])[CH3:24]>CN(C=O)C.O>[OH:25][CH2:23][CH2:24][N:3]1[C:4](=[O:19])[CH2:5][CH2:6][CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[C:2]1=[O:1]
Reactant: CC(O)Cl
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (2.5 g) was dissolved in DMF (dry, 60 mL). 95% NaH (0.24 g) was added. The mixture was stirred for 30 minutes at room temperature. Then, chloroethanol (0.68 mL) was added, and the mixture was stirred over night at room temperature. The reaction mixture was diluted with 300 mL of water and extracted with ethyl acetate (3×60 mL). Organic phases were combined and washed twice with water, and once with brine, then dried over anhydrous magnesium sulfate. Rotary evaporation of solvent yielded crude product, which was purified by silica gel column chromatography (acetic ether:petroleum ether=1:1) to yield 1.1 g of pure title product. 1H NMR (CDCl3, ppm) δ 7.88-7.90 (m, 2H), 7.77-7.79 (m, 2H), 5.06 (dd, 1H, J=5.6, 12.4 Hz), 4.02-4.12 (m, 2H), 3.76-3.80 (m, 2H), 2.94-3.02 (m, 1H), 2.72-2.90 (m, 2H), 2.29-2.31 (m, 1H), 2.14-2.23 (m, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:17]2[C:16]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21](NC(OC(C)(C)C)=O)[CH2:20]3)=[N:15][CH:14]=[N:13][C:12]=2[O:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[Br:8][C:9]1[C:17]2[C:16]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[N:15][CH:14]=[N:13][C:12]=2[O:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NN1CCCC(Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1c(-c2ccccc2)oc2ncnc(OC3CCCNC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a total of 3.4 ml of TFA in several portions at RT to a solution of 1.05 g (2.21 mmol) of tert-butyl rac-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]-1-piperidinecarbamate in 2 ml of dichloromethane, and stir at RT for 2 h. Then dilute with dichloromethane, add satd. sodium hydrogencarbonate solution cautiously to the solution and then wash twice with satd. sodium hydrogencarbonate solution. Dry the organic phase over magnesium sulphate and concentrate under reduced pressure. Stir the oily residue with methanol, filter off the precipitated solid with suction and wash with methanol. Combine mother liquor and wash solution, concentrate under reduced pressure and stir again with a little methanol. Filter off the resulting crystals with suction, wash with methanol and combine with the first crystal fraction. A total of 550 mg (66.4% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.C1C=C[NH+]=CC=1.[Br:21][Br-]Br.O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Br:21][C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13][C:12]=1[CH3:14]
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2nc(C)c(Br)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2-(p-Methoxyphenyl)-4-methylimidazole, (5.0 g, 0.0265 mole), was dissolved in CH3CN (250 ml) at the boiling point. The solution was cooled to room temperature and stirred while a solution of pyridinium bromide perbromide (7.0 g) in CH3CN (70 ml) was added dropwise. A precipitate separated as the addition was completed (30 min) and stirring was continued for 30 minutes. The mixture was poured into water (1.5 L) and the precipitated hydrobromide salt was collected. The filtrate was made basic with saturated Na2CO3 solution and the product was collected, washed with water, and dried to afford 2.45 g, m.p. 183°-187° C. The hydrobromide salt was dissolved in hot CH3CN (75 ml)--H2O (25 ml) and the solution was made basic with saturated Na2CO3 solution. A second crop of product was collected, washed with water, and dried to yield 2.2 g of 35; m.p. 179°-184° C.; 65% combined yield. A sample of the first crop recrystallized from 50% CH3CN melted at 184°-187° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][N:21]=[CH:22][C:14]=1[CH3:13]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: Cc1cnccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: Cc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 60 °C
Yield: 36.6 %

Procedure:
A mixture of 0.62 g of 2-amino-4-(trifluoromethyl)phenol, 0.48 g of 3-methyl isonicotinic acid, 0.86 g of WSC and 5 ml of pyridine was stirred while heating at 60° C. for three hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated. Water was poured into the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 0.38 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-methylisonicotinamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([CH2:7][N:8]([S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])[CH2:25][CH:26]=[CH:27][C:28]([O:30][CH3:31])=[O:29])=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=CCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 110.7 %

Procedure:
A mixture of (6-chloro-naphthalene-2-sulfonyl)glycine tert-butyl ester (17.79 g), methyl 4-bromocrotonate (13.426 g) and potassium carbonate (8.28 g) in DMF (150 ml) was stirred at 50° C. for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated to obtain a residue, which was crystallized from ether to obtain methyl 4-[(tert-butoxycarbonylmethyl)(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenoate (25.13 g) as colorless crystals.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1Cc1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 1-bromomethyl-3-chloro-benzene (0.123 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.107 g, 85%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.78 (s, 2H), 7.16-7.52 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5].F[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([O:13][C:11]2[CH:10]=[CH:9][C:8]([F:14])=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])[C:2]=3[Cl:1])[CH:12]=2)=[C:26]([N+:32]([O-:34])=[O:33])[CH:27]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(O)ccc2F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cc3[N+](=O)[O-])ccc2F)c1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)-N-(2-fluoro-5-hydroxyphenyl)benzamide (2.0 g, 6.01 mmol) and 4-fluoro-3-nitroaniline (940 mg, 6.02 mmol) in N,N-dimethylformamide (12 mL) was added cesium carbonate (2.94 g, 9.02 mmol), and the mixture was stirred at 80° C. for 16 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off and washed with ethyl acetate. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (120 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (120 mL). The aqueous layer was extracted with ethyl acetate (120 mL). The combined organic layer was washed with saturated brine (120 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=20/80→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (1.66 g, 59%) as a yellow powder.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([CH2:40][O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:38])([CH3:37])[CH:31]=[C:30]2[CH3:39]>C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:16](=[O:17])[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:23][C:22]=1[C:27]1[C:28]([CH2:40][O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:38])([CH3:37])[CH:31]=[C:30]2[CH3:39]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cc2ccccc2)cc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Aluminum chloride (97.0 mg, 0.73 mmol) was added to anhydrous dichloroethane (0.5 mL) and the solution was cooled to 0° C. Phenylacetyl chloride (97 μL, 0.73 mmol) and 6-(2-methoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 13-3, 49.7 mg, 0.12 mmol) were added thereto and the reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (53.6 mg) as a pale yellow amorphous product. (Yield 82%)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:25][CH3:26])=[C:7]([CH:13]([NH:15][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:2]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37].[OH-].[Na+]>C(#N)C.CO>[C:36]([N:1]1[CH2:2][CH:3]([C:5]2[C:6]([O:25][CH3:26])=[C:7]([CH:13]([NH:15][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(Cl)c1C1CNC1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(Cl)c1C1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of N-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine (25 mg, 0.064 mmol, from Example 194, Step 8) in acetonitrile (0.3 mL) was treated with DIPEA (28 μL, 0.16 mmol) followed by acetyl chloride (5.4 μL, 0.076 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated with 1N sodium hydroxide (200 μL) and heated briefly with a heat gun. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (6.3 mg, 23%). 1N NMR (300 MHz, DMSO-d6) δ 8.15-8.06 (m, 2H), 7.72 (s, 1H), 5.82-5.61 (m, 1H), 4.56-4.45 (m, 1H), 4.43-4.30 (m, 1H), 4.29-4.17 (m, 1H), 4.14-4.03 (m, 0.5H), 3.86 (s, 3H), 1.84-1.71 (m, 5H), 1.45 (d, J=6.8 Hz, 3H). LCMS for C19H21Cl2N6O2 (M+H)+: m/z=435.1. Found: 435.0.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]1.Br[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1>>[CH:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:53]=[CH:54][C:45]=1[CH2:44][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), from tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate by alkylation with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 721 (M+H)+.