Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=2[F:12])([CH3:4])[CH2:2]1.[CH3:13][Si:14]([CH3:21])([CH3:20])N1C=NC=N1.[N:22]1([Na])[CH:26]=[N:25][CH:24]=[N:23]1.C(O)(=O)C>CN(C)C=O.O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]([O:1][Si:14]([CH3:21])([CH3:20])[CH3:13])([CH2:2][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH3:4]
Reactant: C[Si](C)(C)n1cncn1
Reactant: [Na]n1cncn1
Reactant: CC1(c2ccc(F)cc2F)CO1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(Cn1cncn1)(O[Si](C)(C)C)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
5.13 g (0.03 moles) of 1,2-epoxy-2-(2,4-difluorophenyl)-propane are reacted with 6.35 g (0.045 moles) of 1-(trimethylsilyl)-1,2,4-triazole and 0.14 g (0.0015 moles) of 1,2,4-triazol-1-yl sodium in 40 ml of dimethyl formamide at 80° C. for 3 hours. Then the reaction mixture is cooled to room temperature, neutralized by glacial acetic acid, mixed with 200 ml of water and extracted twice with 50 ml of dichloromethane each. The combined extracts are washed three times with 50 ml of water each, dried over water-free sodium sulfate and evaporated in vacuo. After carrying out a separation as described in Example 5, removal of the solvent and crystallization from n-heptane 6.0 g (64.5%) of the title compound are obtained; m.p.: 51°-53° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:22].[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1
Reactant: OCCCn1cncn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1cncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 1-(3-hydroxypropyl)-[1,2,4]-triazole (119 mg, 0.93 mmol), (EP0060696 A1), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (492 g. 1.8 mmol) in methylene chloride (4 ml) and the mixture stirred for 3 hours at ambient temperature. The mixture was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/32/8). The purified product was triturated with a mixture of pentane and ether, collected by filtration and dried under vacuum to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation. The solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1,2,4-triazol-1-yl)propoxy)quinazoline hydrochloride (121 mg, 39%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[N:11]=1>C(Cl)Cl>[CH2:1]([N:4]([CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[N:11]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(CCl)n1
Reactant: CCCNCCC
Solvent: ClCCl
Product: CCCN(CCC)Cc1nc(CN2C(=O)c3ccccc3C2=O)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
35.6 ml (260 mmol) of dipropylamine were added dropwise at room temperature to a solution of 36 g (130 mmol) of 2-(5-chloromethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione in 300 ml of methylene chloride, whereupon the mixture was stirred at room temperature for 24 hours. The yellow solution was washed with sat. sodium hydrogen carbonate solution, dried with sodium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/aqueous ammonia 19:1). There were obtained 38 g (85%) of 2-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindol-1,3-dione as a beige oil, Rf=0.12 (silica gel, methylene chloride/aqueous ammonia 19:1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH3:3].[CH2:11]([O:13][C:14]([C:16]#[C:17][C:18](OCC)=[O:19])=[O:15])[CH3:12]>>[CH3:1][CH:2]([C:4]1[CH:10]=[CH:9][CH:8]=[C:6]2[C:5]=1[C:18](=[O:19])[CH:17]=[C:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[NH:7]2)[CH3:3]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CC(C)c1cccc(N)c1
Product: CCOC(=O)c1cc(=O)c2c(C(C)C)cccc2[nH]1

Procedure:
Treatment of 3-(1-methylethyl)aniline (6.0 g) with diethylacetylenedicarboxylate (7.1 ml), as described in Example 1b, gave ethyl 5-(1-methylethyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.23 g), mp 176°-178° C., δ (360 MHz, DMSO-d6) 1.19 (6H, d (CH3)2), 1.36 (3H, t, CO2CH2CH3), 4.41 (2H, q, CO2CH2), 4.84 (1H, m, CH(CH3)2), 6.56 (1H, S, 3-H). 7.28 (1H, d, 6-H), 7.58 (1H, t, 7-H), 7.79 (1H, d, 8-H) and 11.80 (1H, bs, NH), and ethyl 7-(1-methylethyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.17 g) mp 186°-188° C., (360 MHz, DMSO-d6) 1.25 (6H, d, (CH3)2),1.35 (3H, t, CH2CH3), 3.00 (1H, m, CH(CH3)2), 4.42 (2H, q, CH2), 6.63 (1H, S, 3-H), 7.29 (1H, d, 6-H), 7.80 (1H, s, 8-H), 8.00 (1H, d, 5-H) and 11.86 (1H, bs, NH).
Reaction SMILES: C([O:8][C:9]1[CH:14]=CN=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]4[CH3:41])[C:25]4[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[N:10]=1)C1C=CC=CC=1.CO.O1CC[CH2:46][CH2:45]1>[OH-].[OH-].[Pd+2]>[CH:32]([N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]3[CH3:41])=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:11]4[NH:10][C:9](=[O:8])[CH:14]=[CH:46][CH:45]=4)=[CH:21][CH:20]=3)=[N:27][C:26]=2[CH2:28]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCc2c(nc(-c3ccc(Nc4nccc(OCc5ccccc5)n4)cc3)nc2N2CCOC[C@@H]2C)C1
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCc2c(nc(-c3ccc(Nc4cccc(=O)[nH]4)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound xa: (S)-4-(benzyloxy)-N-(4-(7-isopropyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyrimidin-2-amine (0.186 g, 0.337 mmol) was purged under nitrogen then added 20% Palladium hydroxide on carbon (2:8, Palladium hydroxide:carbon black, 0.14 g) followed by dry Methanol (4.85 mL, 1.20E2 mmol) Acetic acid (0.46 mL, 8.1 mmol) and dry Tetrahydrofuran (4.85 mL, 59.8 mmol) purged with hydrogen, heated at 40° C. and stirred overnight under an atmosphere of hydrogen. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated, chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.24 (d, J=8.7, 2H), 8.16 (s, 1H), 7.80 (s, 1H), 7.73 (d, J=8.5, 2H), 5.86 (d, J=5.7, 1H), 4.14 (d, J=6.4, 1H), 3.87 (d, J=11.3, 1H), 3.75-3.56 (m, 7H), 3.47-3.39 (m, 2H), 2.88 (dt, J=13.0, 6.5, 1H), 2.74-2.63 (m, 3H), 2.61-2.55 (m, 2H), 2.51 (m, 1H), 1.24 (d, J=6.6, 3H), 1.08 (d, J=6.5, 6H). LC/MS-m/z+462.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH:8]=O)=[O:5].Cl.[NH2:16][OH:17].[C:18]([O-:21])(=O)C.[Na+]>CO>[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:16]([CH:18]=[O:21])[OH:17])=[O:5]
Reactant: O=CCNC(=O)c1cccc(Cl)c1Cl
Reactant: CC(=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=CN(O)CCNC(=O)c1cccc(Cl)c1Cl
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
To a solution of 2,3-dichloro-N-(2-oxo-ethyl)-benzamide (33 g, 0.14 mol) in MeOH (500 mL) was added hydroxylamine hydrochloride (20 g, 0.28 mol) and sodium acetate (23.6 g, 0.28 mol). The mixture was stirred 1.5 h and the MeOH was removed in vacuo. The residue was partioned between saturated NaHCO3 (200 mL) and dichloromethane/MeOH (9:1; 100 mL). The aqueous layer was extracted (4×100 mL) with dichloromethane/MeOH (9:1). The combined organic extracts were washed with brine (50 mL), were dried (Na2SO4) and were concentrated to provide the title compound (34.3 g, 96%) as a 1:1 mixture of cis and trans isomers as a clear, pale brown oil. 1H NMR (400 MHz, CD3OD): δ 7.66 (m, 1H); 7.45 (m, 3H); 6.78 (t, j=4.1 Hz, 0.5H); 4.30 (d, j=4.1 Hz, 1H); 4.12 (d, j=5.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7](O)[C:6]=2[CH:11]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: Oc1noc2ccc(Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1ccc2onc(Cl)c2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a suspension of 5-chloro-3-hydroxy-1,2-benzisoxazole (100 g) in phosphorus oxychloride (80 ml) was added pyridine (48 ml) dropwise over 1 hours with stirring at room temperature, and the mixture was then refluxed for 5 hours. The reaction mixture was added to ice water (500 ml) and extracted with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure and the title compound (102 g, 92%) was obtained by recrystallizng the residue from petroleum ether as a colorless needle.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.S(Cl)(Cl)=O.[OH-].[Na+].Cl.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1>COCCOC.O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:25]3[CH2:28][CH:27]([OH:29])[CH2:26]3)=[O:17])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC1CNC1
Reactant: O=C(O)CCOCCc1ccc2sccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Product: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
In 75 mL of 1,2-dimethoxyethane was dissolved 50.0 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid. Thereto was added 26.1 g of thionyl chloride, which was then refluxed for 2 hours. After cooling, this reaction solution was dropwise added to a mixed solution of 125 mL of water, 20.0 g of sodium hydroxide and 25.2 g of 3-azetidinol hydrochloride at −5 to 10° C., which was then stirred at 0 to 15° C. for 30 minutes. Thereto was added 75 mL of water, which was heated to 40° C. and dissolved. After cooling, the precipitate was collected by filtration to provide 56.5 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol as white solid form.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(N1[CH2:29][CH2:28][CH2:27]C1=O)C.C1(CBr)CC1.C(N(CC)C(C)C)(C)C.Cl>O>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:27]4[CH2:28][CH2:29]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: CCN1CCCC1=O
Agent: BrCC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 54.5 °C
Yield: 100.8 %

Procedure:
A mixture of noroxymorphone (62 Kg), N-ethyl-2-pyrrolidinone (186 kg), cyclopropymethyl bromide (37.8 kg) and N,N-diisopropylethylamine (36.2 kg) was heated to 52-57° C. for 24 hours and 45 min. The mixture was then diluted with a solution prepared by mixing hydrochloric acid 37% (30 kg) and water (82 kg). Low boiling compounds were removed by distillation under vacuum keeping the temperature below 70° C. After cooling to 25-30° C. the mixture was further diluted with water (1975 kg). Ammonium hydroxide 4% (206 kg) was then added over three hours till pH=9-10 to precipitate the product. The solid was filtered, washed with water (2×124 kg) and dried under vacuum at 60° C. obtaining 71.3 kg of naltrexone (molar yield 89.6%). HPLC analysis (% by area): naltrexone 99.45%, noroxymorphone 0.16%, 3-cyclopropylmethylnaltrexone 0.28%
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[O:49][CH3:50])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>O>[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[O:49][CH3:50])=[CH:22][CH:23]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(OC)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(OC)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-tert-butoxyphenyl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.53 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.10 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.095 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 26%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:51]([NH2:62])[C:52]1[CH:61]=[CH:60][C:57]([O:58][CH3:59])=[C:54]([O:55][CH3:56])[CH:53]=1>CN(C=O)C>[CH3:56][O:55][C:54]1[CH:53]=[C:52]([CH:61]=[CH:60][C:57]=1[O:58][CH3:59])[CH2:51][NH:62][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[NH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(I)ccc1NC1CCOCC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(I)ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 14.22 g of 5-iodo-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid, 18.4 g of HBTU, 21.28 g of DIEA and 9.18 g of veratrylamine in 200 ml of DMF is stirred overnight at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in 3000 mL of EtOAc. The solution is washed with aqueous 0.5N HCl solution, with saturated aqueous NaHCO3 solution, and then with saturated aqueous NaCl solution. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure to give 18 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:11]([CH2:12][C:13]2[CH:31]=[CH:30][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])=[CH:35][CH:34]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Reactant: Fc1ccc(CBr)cc1
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 4-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:46]=[CH:45][C:39]([O:40][CH2:41][C:42](O)=[O:43])=[CH:38][CH:37]=2)[S:30]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:40][CH2:41][C:42]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:43])=[CH:45][CH:46]=2)[S:30]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 84.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-trifluoromethylphenoxy)phenyl]-N-methylcarbamate (0.68 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.73 g), diethyl cyanophosphonate (0.49 g), triethylamine (0.30 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (0.97 g).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[F:30])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:32]([O:36][C:37]([CH2:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[C:49](O)=[O:50])=[O:38])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:32]([O:36][C:37]([CH2:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[C:49]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:22]([F:30])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27])[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:50])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Yield: 65.8 %

Procedure:
The procedure of Example 77 was followed using the product of Example 106 (400.0 mg, 0.90 mmol), 1-[(tert-butyloxycarbonyl)methyl]indole-2-carboxylic acid (200 mg, 0.73 mmol), NMM (0.1 ml), HOBt (246 mg, 1.63 mmol), and EDAC (304 mg, 1.60 mmol) in methylene chloride to prepare the titled product (341 mg, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)=[CH:6][CH:5]=1)([O-])=O.O.[ClH:18].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[ClH:18].[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1N[C@@H](Cc2ccc([N+](=O)[O-])cc2)CO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
A suspension of the product from step (c) (0.79 g) and 10% palladium on carbon (0.26 g) in a mixture of ethanol (15 ml), water (11 ml), ethyl acetate (2.0 ml) and aqu. 2N HCl (2.3 ml) was stirred under 1 atmos. pressure of hydrogen until uptake ceased. The mixture was filtered through Hyflo and the filtrate evaporated in vacuo to give the desired product as a pale yellow foam (0.79 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1.[CH3:12][Mg]Br.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])([CH3:12])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: CC(=O)c1nc(Cl)ncc1F
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A stirred, −78° C. solution of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)ethanone (10.06 g, 57.6 mmol) in tetrahydrofuran (100 mL) under nitrogen is reacted with a 3 M solution of methyl magnesium bromide in diethyl ether (124 mL, 72.04 mmol) and the resulting mixture is stirred at −78° C. for 20 minutes. The reaction is quenched with aqueous saturated ammonium chloride and the mixture is warmed to room temperature. The reaction mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under vacuum. The crude product is purified over silica gel with a 30 minute, 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (7.06 g, 64%). ES/MS (m/e): (35Cl/37Cl) 191/193 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].Cl.[CH3:7][C@H:8]1[NH:13][C@@H:12]([CH3:14])[CH2:11][N:10]([CH2:15][CH2:16][CH2:17]O)[CH2:9]1>>[ClH:3].[ClH:5].[CH3:7][C@H:8]1[NH:13][C@@H:12]([CH3:14])[CH2:11][N:10]([CH2:15][CH2:16][CH2:17][Cl:5])[CH2:9]1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H]1CN(CCCO)C[C@H](C)N1
Agent: Cl
Product: C[C@@H]1CN(CCCCl)C[C@H](C)N1

Procedure:
Thionyl chloride (300 g) was slowly added to 3-(3,5-cis-dimethylpiperazino)propanol dihydrochloride (200 g). The reaction was gently refluxed for an hour followed by removal of excess thionyl chloride by vacuum distillation. The resulting solid was washed with several portions of benzene then several portions of ether, m.p. 291°-292°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27]2.C(=O)(O)[O-].[Na+]>C(O)C>[CH:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][N:27]2[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: C1CC2CCC1CN2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2nc(N3CC4CCC3CC4)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-nitroquinoline (5.0 g, 24 mmol, Example 1, Step B), 2-azabicyclo[2.2.2]octane p-toluenesulfonic acid salt (10.2 g, 36 mmol) and sodium bicarbonate (5.1 g, 60 mmol) were mixed in absolute ethanol (100 mL) and then heated at reflux for 24 h. The reaction mixture was cooled to r.t., and the solvent removed under vacuum. The solids were taken up in EtOAc (750 mL). The mixture was transferred to a separatory funnel washed with water (3×100 mL) then brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum to afford the product as a yellow solid, MS: m/z 284 (MH+) which was used without further purification.