Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:32]([N:26]1[CH2:27][CH:11]2[CH:12]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (5 drops) is added to a solution of 4,4-diphenyl-2-cyclohexen-1-one (155 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (202 cc) in dry dichloromethane (1000 cc), and the reaction mixture is heated to reflux for 45 minutes. N-Butoxymethyl-N-(trimethylsilylmethyl)benzylamine (50 cc) and trifluoroacetic acid (3 drops) are added and the mixture is stirred for a further 45 minutes under reflux before N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (25 cc) and trifluoroacetic acid (3 drops) are added again. The reaction mixture is stirred under reflux for 45 minutes, then treated with potassium carbonate (50 g), filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in isopropyl ether (200 cc) and the solution cooled to 0° C. for 1 hour. The crystals are drained, washed with isopropyl ether (2×15 cc) and dried to give (3aRS,7aRS)-2-benzyl-7,7-diphenylperhydro-4-isoindolone (193 g) in the form of white crystals, m.p. 132° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[NH:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[C@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 1-bromo-4-bromomethylbenzene (500 mg, 2.0 mmol), cis-2,6-dimethylpiperidine (0.30 mL, 2.2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in acetonitrile (20 mL) was heated under reflux for 2 h. The reaction mixture was allowed to cool to ambient temperature, the solid removed by filtration and the filtrate evaporated in vacuo. The resultant residue was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title compound as a pale brown oil (464 mg, 82%). 1H NMR (CDCl3, 300 MHz): 7.40 (d, J=8.3 Hz, 2H), 7.27 (d, J=7.0 Hz, 2H), 3.71 (s, 2H), 2.56-2.36 (m, 2H), 1.68-1.61 (m, 1H), 1.61-1.47 (m, 2H), 1.33-1.24 (m, 3H), 1.01 (d, J=6.2 Hz, 6H). LCMS (Method B): RT=0.8 min, M+H+=282/284.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CN([CH:14]=[O:15])C.C1[CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:20][O:19][CH2:18][CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:14]=[O:15]
Reactant: C1CCOC1
Reactant: c1c[nH]cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: COCCn1ccnc1C=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of the imidazole (342 mg, 2.71 mmol) in THF (3.5 mL) was cooled to −78° C. under nitrogen and n-BuLi (2.5M in hexanes, 1.4 mL, 3.5 mmol) was added. The resulting bright yellow solution was stirred at 0° C. for 10 minutes, then DMF (0.5 mL, 6.5 mmol) was added. The reaction was stirred at room temperature for 45 minutes, then was quenched by the addition of saturated aqueous NH4Cl (5 mL). The layers were separated and the aqueous solution was extracted with CH2Cl2 (10 mL×2). The organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2MeOH, 32:1) gave the aldehyde as a yellow liquid (1:1 with DMF, 254 mg, 1.12 mmol, 41%). 1H NMR (CDCl3) δ 3.30 (s, 3H), 3.66 (t, 2H, J=5.1 Hz), 4.58 (t, 2H, J=5.0 Hz), 7.26 (s, 1H), 7.27 (s, 1H), 9.80 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[Cl:1][C:2]1[C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OC1CCCCC1
Product: Nc1cc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 84.9 %

Procedure:
Into a solution of 20.02 g of 4,5-dichloro-2-nitroaniline and 8.70 g of piperazine in 100 ml of cyclohexanol, 12.80 g of sodium carbonate was added and stirred at 150° C. for 14 hours. Cooling the reaction liquid to room temperature, water was added and the system was extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. Thus obtained residue was washed with diisopropyl ether to provide 21.07 g of 4-chloro-2-nitro-5-(piperazin-1-yl) aniline as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1.[C:28](#[N:31])[CH:29]=[CH2:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:24][C:22]1([CH3:25])[CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([C:7]3[C:6]4[C:10](=[C:2](/[CH:30]=[CH:29]/[C:28]#[N:31])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21]1
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cccc34)n2)CC(C)(C)N1
Reactant: C=CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(/C=C/C#N)cccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 228 and acrylonitrile, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:28])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([Cl:28])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Product: O=C(Cl)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
5-Bromo-2-(4-trifluoromethoxy-benzenesulfonylamino)-benzoic acid (3.27 g, 7.4 mmol) was suspended in thionyl chloride (30 mL). The mixture was heated to reflux for 4 hours. The solvent was removed to dryness. The residue was dissolved in anhydrous ethyl acetate and solvent removed (2×20 mL). The solid was dried at 40° C. in vacuum oven overnight.
Reaction SMILES: [Si](O[C@@H]1[C@@H](CO[Si](C(C)(C)C)(C)C)O[C@@H](N2C3N=CN=C(OC4C=CC([N+]([O-])=O)=CC=4)C=3N=C2)C1)(C(C)(C)C)(C)C.N1(O[C:52]2[C:53]3[N:54]=[CH:55][N:56]([C:87]=3[N:88]=[CH:89][N:90]=2)[C@@H:57]2[O:86][C@H:76]([CH2:77][O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:81])[CH3:80])[C@@H:67]([O:68][Si:69]([C:72]([CH3:75])([CH3:74])[CH3:73])([CH3:71])[CH3:70])[C@H:58]2[O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:97][C:98]1[CH:99]=[CH:100][CH:101]=[C:102]2[C:107]=1[N:106]=[CH:105][CH:104]=[CH:103]2>COCCOC>[N:106]1[C:107]2[C:102](=[CH:101][CH:100]=[CH:99][C:98]=2[O:97][C:52]2[C:53]3[N:54]=[CH:55][N:56]([C:87]=3[N:88]=[CH:89][N:90]=2)[C@@H:57]2[O:86][C@H:76]([CH2:77][O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:81])[CH3:80])[C@@H:67]([O:68][Si:69]([C:72]([CH3:73])([CH3:74])[CH3:75])([CH3:70])[CH3:71])[C@H:58]2[O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:61])[CH3:62])[CH:103]=[CH:104][CH:105]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Oc1cccc2cccnc12
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4cccc5cccnc45)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 72.4 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this quinolinyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)inosine (27) (71.8 mg, 0.099 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and 8-hydroxyquinoline (16.0 mg, 0.110 mmol) in dry DME (1.0 mL) at 85° C. for 1 h. Chromatographic purification (SiO2, elution with 50% EtOAc in hexanes) afforded 52.9 mg (72% yield) of the title compound as a white foam. Rf (50% EtOAc in hexanes)=0.58. 1H NMR (500 MHz, CDCl3): δ 8.74 (m, 1H, Ar—H), 8.48 (s, 1H, Ar—H), 8.33 (s, 1H, Ar—H), 8.20 (m, 1H, Ar—H), 7.79 (d, 1H, Ar—H, J=8.3), 7.67-7.60 (m, 2H, Ar—H), 7.39 (dd, 1H, Ar—H, J=8.5, 4.2), 6.13 (d, 1H, H-1′, J=4.4), 4.63 (t, 1H, H-2′, J=4.4), 4.37 (t, 1H, H-3′, J=4.1), 4.17 (m, 1H, H-4′), 4.07 (dd, 1H, H-5′, J=11.2, 3.4), 3.83 (dd, 1H, H-5′, J=11.2, 2.4), 0.97, 0.94, 0.84 (3S, 27H, tert-Bu), 0.17, 0.15, 0.12, 0.11, 0.0, −0.11 (6 s, 18H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 161.0, 152.9, 151.9, 150.2, 149.1, 141.9, 141.5, 135.9, 129.7, 126.4, 125.9, 122.0, 121.6, 121.5, 88.7, 85.1, 76.2, 71.5, 62.3, 26.1, 25.8, 25.7, 18.6, 18.1, 17.9, −4.3, −4.7, −4.73, −4.9, −5.3, −5.4. FAB HRMS calcd for C37H60N5O5Si3 (M++H) 738.3902. found 738.3885.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3]1=[O:22].[OH:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3](=[O:22])[C@@H:2]([NH:1][C:32](=[O:33])[C:25]2[C:24]([OH:23])=[C:29]([O:30][CH3:31])[CH:28]=[CH:27][N:26]=2)[CH2:10][O:9][CH2:8]1)[CH:13]([CH3:14])[CH3:15]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CC(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a mixture of (3S,7S,8S,9S)-3-amino-7,8-diisobutoxy-9-methyl-1,5-dioxonan-2-one (170 mg, 0.536 mmol), 3-hydroxy-4-methoxypicolinic acid (136 mg, 0.803 mmol) and HATU (336 mg, 0.857 mmol) in a vial was added CH2Cl2 (3 mL), followed by 4-methylmorpholine (0.353 mL, 3.21 mmol), and the resulting suspension was stirred at room temperature for 3 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white solid (176 mg, 70%): 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 8.68 (d, J=8.0 Hz, 1H), 8.00 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.10-5.00 (m, 1H), 4.97 (dt, J=12.6, 6.3 Hz, 1H), 4.10-4.01 (m, 1H), 3.94 (s, 3H), 3.87-3.78 (m, 2H), 3.71 (dd, J=8.4, 6.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.38-3.28 (m, 2H), 3.28-3.17 (m, 3H), 1.90-1.76 (m, 2H), 1.45 (t, J=5.8 Hz, 3H), 0.98-0.88 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 170.33, 168.95, 155.38, 148.76, 140.66, 130.23, 109.58, 84.84, 83.75, 80.60, 77.74, 75.32, 73.97, 73.23, 56.11, 52.19, 29.13, 28.89, 19.60, 19.48, 19.47, 19.39, 18.66; ESIMS m/z 469.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][OH:25])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[Si:35]([O:25][CH2:24][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C:10]1=[O:23])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution (20 mL) of tert-butyl 7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-6-oxo-1,4-oxazepane-4-carboxylate (1.27 g) in DMF were added imidazole (266 mg) and tert-butyldimethylchlorosilane (540 mg), and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, the mixture was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.35 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([O:12][CH3:13])[C:5]=1[N:14]=[CH:15]OCC.O.[NH2:21][NH2:22]>C(O)C>[NH2:21][N:22]1[C:3](=[O:2])[C:4]2[C:5](=[C:6]([O:12][CH3:13])[C:7]([Cl:11])=[CH:8][C:9]=2[Cl:10])[N:14]=[CH:15]1
Reactant: CCOC=Nc1c(OC)c(Cl)cc(Cl)c1C(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1c(Cl)cc(Cl)c2c(=O)n(N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of the imidate 5-2 (400 mg, 1.31 mmol) in ethanol (12 mL), was added under an argon atmosphere, hydrazine hydrate (1.8 mL, 57.8 mmol). After 15 min, the solution was warmed to room temperature and stirred for a further 2 h. The thick suspension was diluted with ethanol and filtered. The solid was washed with cold ethanol and dried under vacuum to give 3-amino-5,7-dichloro-8-methoxy-3H-quinazolin-4-one (5-3) as a white fluffy solid (289 mg, 85%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:14][C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+].CN([CH:25]=[O:26])C>>[CH:25]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:26]
Reactant: CCCCCCCCOc1ccsc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccsc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the stirred solution of anhydrous DMF (10 mL) at 0° C. in 100 mL three neck flask under Nitrogen atmosphere, POCl3 (0.53 mL, 5.76 mmol) was added dropwise for 5 minutes. After addition, the reaction mixture was stirred at room temperature for 1 hour. Then 3-octyloxythiophene (1.02 g, 4.80 mmol) in 2 mL DMF was added dropwise at 0° C. for 5 minutes. This solution was stirred at 70° C. for 90 minutes and poured it into ice water and then slowly neutralized with 10% NaOH solution (20 mL). The resultant mixture was heated in a steam-bath for 20 min. The aqueous layer was extracted with CHCl3 (3×50 mL), followed by drying over anhydrous Na2SO4. After the removal of solvents, the crude mixture was chromatographed on silica gel (10% ethyl acetate in hexane) to give 3′ as a colourless oil. (1.0 g, 86%). 1H NMR (CDCl3, 300 MHz, ppm): δ 10.01 (s, 1H), 7.62 (d, 1H, 5.4 Hz), 6.84 (d, 1H, 5.4 Hz), 4.15 (t, 2H, 6.6 Hz), 1.76-1.86 (m, 2H), 1.29-1.46 (m, 10H), 0.89 (t, 3H, 6.6 Hz). M/e 240.12.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]2([C:25]3[CH:34]=[C:33]([O:35][CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH:32]=[CH:31][C:26]=3[C:27]([NH:29][NH2:30])=[O:28])[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.C(=O)(O)[O-].[Na+]>C(OC(OCC)OCC)C>[O:28]1[CH:1]=[N:30][N:29]=[C:27]1[C:26]1[CH:31]=[CH:32][C:33]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[CH:34][C:25]=1[C:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][CH2:21]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: c1ccc(C2(c3cc(OCc4ccc5ccccc5n4)ccc3-c3nnco3)CC3CCC2C3)cc1
Reaction time: 0.5 h

Procedure:
A catalytic amount of p-TSA (˜3 mg) was added to a stirred suspension of 4d HCl salt (54.6 mg, 0.10 mmol) in triethylorthoformate (600 μL) at room temperature. After 30 min, 1N hydrochloric acid (600 μL) was added, and the resulting solution was aged for an additional 45 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TFA as modifier). Lyophilization of the purified fractions afforded the title compound Sc, m/z (ES) 474 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl>O>[C:1]1([CH2:7][O:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 54 parts of (phenylmethyl)carbonochloridate, 60 parts of ethyl 4-piperidinepropanoate, 31.8 parts of sodium carbonate and 600 parts of trichloromethane was stirred overnight at room temperature. Water was added and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 71 parts (74%) of ethyl 1-(phenylmethoxycarbonyl)-4-piperidinepropanoate as a residue (interm. 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:25])[N:14]([CH3:24])[N:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]=1[S:18][CH3:19])[CH3:2].C(=O)([O-])[OH:27].[Na+].ClC1C=C(C=CC=1)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:25])[N:14]([CH3:24])[N:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]=1[S:18]([CH3:19])=[O:27])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(SC)c(C(F)(F)F)nn(C)c1=O
Reactant: O=C([O-])O
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C(F)(F)F)nn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a 50 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfanyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-46)-(1)-39) (0.51 g) and chloroform (12.5 ml) were added at room temperature. Sodium hydrogen carbonate (0.46 g) and meta-chlorobenzoic acid (0.48 g) was added and the resulting mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was poured into water (20 ml), added sodium sulfite (0.3 g), and extracted with t-butyl methyl ether (40 ml) 2 times. Then, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=3:1 to hexane: ethyl acetate=1:1) to give 0.461 g of 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-39).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH2:42]([N:49]1[CH2:54][CH2:53][CH:52]([NH2:55])[CH2:51][CH2:50]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)(Cl)Cl.O>[CH2:42]([N:49]1[CH2:54][CH2:53][CH:52]([NH:55][C:34]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[O:40])[CH2:51][CH2:50]1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (97 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (142 mg, yield 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH:13]=[O:14].[H-].[Na+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C)C=O.O>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH:13]=[O:14])=[C:7]2[CH3:12])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc2[nH]c(C)c(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(C=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a solution of 5-methoxy-2-methyl-1H-indole-3carboxaldehyde (20 g, 106 mmol) in 210 ml of dry dimethylformamide is added oil free sodium hydride (2.7 g, 111 mmol). The reaction mixture is stirred for five hours at which time it is cooled to -60° C., and freshly distilled 4-chlorobenzoyl chloride (14.4 ml, 117 mmol) is added dropwise. It is stirred for an additional 10 minutes and worked up by pouring the cold paste into cold ethyl acetate and water. The organic phase is washed once with dilute sodium bicarbonate solution, once again with water, and once with a saturated solution of sodium chloride. It is further dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid which is stirred vigorously with 50 ml of methanol for two hours. The solid is filtered and dried to give 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde (28.7 g, 82.5%). A portion which is recrystallized from ethyl acetate has a mp of 150.5°-151.5° C.