Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][C:24]([CH3:29])([CH3:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:12]([C:9]2[N:10]=[CH:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:14])[C:24]([CH3:29])([CH3:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncn(-c3ccccc3)n2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 420 mg (2.22 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carboxylic acid, 500 mg (2.22 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, 750 mg (2.22 mmol) TBTU and 500 μL (2.91 mmol) DIPEA in 5 mL DMF was stirred at RT for 2 h.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1)[CH3:2].O.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[CH:50]=O>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:5]2[CH:50]([C:49]([O:53][CH2:54][CH3:55])=[O:52])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
2-Ethyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (7.48 g) is dissolved in tetrahydrofuran (60 ml) to which is added ethyl glyoxylate hydrate (1.56 g). The reaction mixture is stirred overnight at room temperature and then refluxed for one hour. The solution is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(1 -trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.54 g) as a foam, characterized as its oxalate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.CO.C(OCC)C.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Nc1ccnc(Cl)c1
Solvent: CCOCC
Solvent: CO
Product: CN1CCN(c2cc(N)ccn2)CC1
Temperature: 135 °C
Yield: 18.6 %

Procedure:
4-Amino-2-chloropyridine (180 mg, 1.4 mmol) was dissolved in 1-methylpiperazine (1 ml), followed by heating at 135° C. for 16 hours in a pressure vessel. After cooling to room temperature, methanol (2 ml) and diethyl ether (2 ml) were added, and the deposited precipitate was filtered off. The resulting solid was washed with cooled diethyl ether followed by drying, to obtain a colorless crystal powder (50 mg, 18.6% yield).
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][C:16]([F:19])=[CH:15][C:14]=1[F:20].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=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: Fc1ccc(CBr)c(F)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=C1c2ccccc2CN1Cc1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-2,4-difluoro-benzene (0.248 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.11 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2,4-difluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.199 g, 77%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.84 (s, 2H), 6.85 (m, 2H), 7.35-7.54 (m, 4H), 7.86 (d, 1H).
Reaction SMILES: C(OC([N:8]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[C:19]([CH3:25])=[C:20]([C:22]([OH:24])=O)[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.Cl.[N+:34]([C:37]1[CH:38]=[C:39]([NH:43][NH2:44])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]>>[N+:34]([C:37]1[CH:38]=[C:39]([NH:43][NH:44][C:22]([C:20]2[O:21][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:18]=3[C:19]=2[CH3:25])=[O:24])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: Cc1c(C(=O)O)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Agent: Cl
Product: Cc1c(C(=O)NNc2cccc([N+](=O)[O-])c2)oc2cccc(OCCCNCc3cccnc3)c12

Procedure:
This compound was prepared from 4-[3-(tert-butoxycarbonyl-pyridin-3-ylmethyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid (Example 139-a) and 3-nitrophenylhydrazine hydrochloride in a similar manner to Example 139-b and 139-c. ESI-MS: m/z 476 (MH+), 1H-NMR δ: 2.07 (2H, tt, J=5.9, 6.8 Hz), 2.69 (3H, s), 2.88 (2H, t, J=6.8 Hz), 3.84 (2H, s), 4.18 (2H, t, J=5.9 Hz), 6.51 (1H, m), 6.66 (1H, d, J=7.9 Hz), 7.07 (1H, d, J=7.9 Hz), 7.20-7.42 (4H, m), 7.67 (1H, m), 7.74-7.77 (2H, m), 8.41 (1H, m), 8.49 (1H, m), 8.56 (1H, m).
Reaction SMILES: [OH-:1].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][C:28]#N)[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:30].Cl>CO.C(Cl)Cl>[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:1])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
A 5 N aqueous sodium hydroxide solution (200 mL) was added to a solution of (1-trityl-1H-imidazol-4-yl)acetonitrile (33 g) in methanol (100 mL), and the mixture was heated to reflux for 4 hours. To this reaction solution, water and methylene chloride were added, and the mixture was neutralized with a 1 N aqueous hydrochloric acid solution. Methanol was added thereto until insoluble matter was dissolved, and the organic layer was then separated. The aqueous layer was further subjected to extraction three times with a methylene chloride:methanol (9:1) mixed solvent, and the extracts were combined with the foregoing separated organic layer and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained white solid was washed with a hexane-diisopropyl ether mixed solvent. The solid was dried under reduced pressure to obtain the title compound (34 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: FC(F)(F)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
5-Trifluoromethylindole (D5, 1.0 g, 0.0057 mole) in glacial acetic acid (25 ml) was treated with sodium cyanoborohydride (1.7 g, 0.027 mole) under argon and stirred at room temperature for 2 hours. The mixture was poured into water (200 ml), basified with 40% aqueous sodium hydroxide solution, extracted into DCM, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% ethyl acetate/60-80° petroleum ether to afford the title compound (0.45 g, 45%) as a pale yellow oil.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][C@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 76%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>CN(C)C=O>[CH3:24][Si:25]([CH3:27])([CH3:26])[O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Yield: 90 %

Procedure:
The mixture of 4-(4-oxo-Piperidin-1-yl)-nitrobenzene (126 mmol), triethylamine (630 mmol), trimethylsilylchloride (375.0 mmol) in dimethylformamide was heated at 70° C. for 24 h. The solvent was removed under vacuum and to the residual mass was extracted with the ethyl acetate water mixture. The combined organic layer was dried and after removal of the solvent afforded title compound as a solid in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10]C(=O)[C@@H]1CC(C)(C)C(=O)N1CC.[CH2:23]([N:25]1[C:32](=[O:33])[C:31]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])[CH3:24].C(N1C(=O)C(C)(C)C[C@H]1C(O)=O)C.[CH2:61]([N:63]1[CH:67]([CH2:68][O:69][C:70]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:66][C:65]([CH2:96]C2C=CC=CC=2)([CH2:89]C2C=CC=CC=2)[C:64]1=[O:103])[CH3:62]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:27](=[O:29])[C@@H:26]1[CH2:30][C:31]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:32](=[O:33])[N:25]1[CH2:23][CH3:24].[CH2:23]([N:25]1[C:32](=[O:33])[C:31]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])[CH3:24].[CH2:61]([N:63]1[CH:67]([CH2:68][O:69][C:70]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:66][C:65]([CH3:96])([CH3:89])[C:64]1=[O:103])[CH3:62]
Reactant: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Reactant: CCN1C(=O)C(Cc2ccccc2)(Cc2ccccc2)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN1C(=O)C(C)(C)C[C@H]1C(=O)O
Agent: CCN1C(=O)C(Cc2ccccc2)(Cc2ccccc2)C[C@H]1C(=O)O
Product: CCN1C(=O)C(C)(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCN1C(=O)C(Cc2ccccc2)(Cc2ccccc2)C[C@H]1C(=O)NCc1ccc(F)cc1Cl

Procedure:
N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-4,4-bis(phenylmethyl)prolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (E130) but using 1-ethyl-5-oxo-4,4-bis(phenylmethyl)proline in the place of 1-ethyl-4,4-dimethyl-5-oxoproline. 1-Ethyl-5-oxo-4,4-bis(phenylmethyl)proline was prepared in a manner analogous to that described for 1-ethyl-4,4-dimethyl-5-oxoproline in example 130 above but using 1-ethyl-3,3-bis(phenylmethyl)-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (isolated as a side-product in method B, Example 37) in place of 1-ethyl-3,3-dimethyl-5-{[(tri phenyl methyl)oxy]methyl}-2-pyrrolidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH:5]=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.N1CCCCC1>O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH:5]=[CH:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C)c(OC)c(C=O)c1C
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: COc1cc(C)c(OC)c(C=CC(=O)O)c1C
Yield: 67.4 %

Procedure:
A mixture of 2,5-dimethoxy-3,6-dimethylbenzaldehyde (5.0 g), malonic acid (3.8 g), pyridine (6 ml) and piperidine (0.3 ml) was refluxed for 25 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and recrystallized from ethanol to obtain 2,5-dimethoxy-3,6-dimethylcinnamic acid (4.1 g) (Compound A-22). The physical properties and NMR spectrum data thereof are shown in Table 1.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].I[CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH3:12]
Reactant: Oc1cccc(F)c1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cccc(F)c1Br
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromo-3-fluorophenol (5.000 g; 26.20 mmol), iodoethane (8.166 g; 52.40 mmol), and K2CO3 (4.342 g; 31.40 mmol) in anh. DMF (100 ml) was heated to 80° C., under nitrogen, for 1.5 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-bromo-1-ethoxy-3-fluorobenzene as a yellow oil. LC-MS (conditions A): tR=0.88 min.; no ionisation.
Reaction SMILES: [Br-:1].C[C:3](C)([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:36]=[CH:35][C:11]([O:12][CH2:13][CH2:14][CH2:15][P+:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(CCCOC1C=CC(OCCC[Br:83])=CC=1)C(OCC)=[O:65]>C(#N)C>[OH:65][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:35]=[CH:36][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:9][CH:10]=1.[Br:1][Br:83].[C:29]1([P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(C)(C)CCCOc1ccc(OCCCBr)cc1
Reactant: CCOC(=O)C(C)(C)CCCOc1ccc(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrBr
Product: CCOC(=O)CCCCOc1ccc(OCCCO)cc1

Procedure:
The 3-[4-(4,4-dimethyl-4-ethoxycarbonylbutoxy)phenoxy]propyltriphenylphosphonium bromide used as starting material was prepared by reacting triphenylphosphine in acetonitrile, at reflux, with ethyl 2,2-dimethyl-5-[4-(3-bromopropyloxy)phenoxy]pentanoate, itself obtained from ethyl 5-[4-(3-hydroxypropyloxy)phenoxy]pentanoate and bromine in acetonitrile in the presence of triphenylphosphine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][S:12]([C:15]1[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][N:20]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 4-fluoronitrobenzene (4.74 g) and 6-(methylsulfonyl)pyridin-3-ol (6.4 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (9.3 g), and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (9.88 g, yield 100%) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C1COCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:4]=[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:2]([C:34]([C:33]2[CH:37]=[C:38]([S:41][CH3:42])[CH:39]=[CH:40][C:32]=2[Cl:31])=[O:35])=[CH:7][N:6]=1
Reactant: Fc1ccc(Oc2ncc(Br)c(Oc3ccc(F)cc3F)n2)c(F)c1
Reactant: CSc1ccc(Cl)c(C(=O)Cl)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1ccc(Cl)c(C(=O)c2cnc(Oc3ccc(F)cc3F)nc2Oc2ccc(F)cc2F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To 5-bromo-2,4-bis-(2,4-difluoro-phenoxy)-pyrimidine (3.83 g, 9.23 mmol) in dry THF at 0° C. was added isopropyl magnesium chloride (6.93 mL of 2.0 M solution in THF, 13.85 mmol). The resulting mixture was stirred at 0° C. for 20 minutes. A solution of 2-chloro-5-methylsulfanyl-benzoyl chloride (4.27 g, 19.33 mmol) in 20 mL dry THF was added dropwise, with stirring at 0° C. continued for one hour. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 5-25%) to give 3.015 g of [2,4-bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-(2-chloro-5-methylsulfanyl-phenyl)-methanone, MS (M+H)=521.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Br:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[C:9](\[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[O:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Reactant: O=Cc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=C/c1ccc(Br)cc1)C(=O)c1ccccc1O
Yield: 57.4 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (289 mg, 1.2 mmol), 4-bromobenzaldehyde (226 mg, 1.2 mmol), 20.0 mL benzene, piperidine (10 μL, 0.1 mmol) and glacial acetic acid (5.6 μL, 0.1 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 278 mg (57%) of clear crystals. mp=98-100° C.; IR (film) 2978.4; 1712.8; 1629.0; 1155.7 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.84 (bs, 1H); 7.78 (s, 1H); 7.52-7.48 (m, 2H); 7.43-7.21 (AA′BB′, 4H); 7.04 (d, J=7.0 Hz, 1H); 6.83 (t, J=7.3 Hz, 1H); 1.41 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.3, 163.5, 162.9, 140.8, 137.4, 132.5, 132.3, 131.9, 131.8, 131.6, 125.3, 120.0, 119.7, 118.7, 83.1, 28.1; LRMS (electrospray): Mass calculated for C20H19BrO4, [M]+, 402.1, 404.0. Found [M+23]+, 424.7, 426.8. An NOE difference experiment was conducted for this compound and a positive NOE was seen for the alkene proton when the tert-butyl signal was irradiated and a positive NOE was seen for the tert-butyl signal upon irradiation of the alkene proton. This compound was further characterized by X-ray crystal structure, see S56.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([S:19][CH2:20][C:21]([OH:23])=O)[N:13]=[C:12]([CH3:24])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=N[CH2:36][CH2:37][CH2:38][N:39](C)C.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([S:19][CH2:20][C:21]([NH:39][CH:38]1[CH2:36][CH2:37]1)=[O:23])[N:13]=[C:12]([CH3:24])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc2c(c(SCC(=O)O)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc2c(c(SCC(=O)NC3CC3)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (20 mg, 0.05 mmol), EDCI (18 mg, 0.10 mmol), HOBT (13 mg, 0.10 mmol) and cyclopropylamine (0.004 mL, 0.06 mmol) in CH2Cl2 (5 mL) was added TEA (0.02 mL, 0.14 mmol). The reaction solution was stirred at room temperature for 24 h before the mixture was diluted with CH2Cl2, washed with 0.5N HCl, saturated aqueous NaHCO3, brine and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide 2-[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]-N-cyclopropylacetaide (13 mg, 59%): LCMS RT: 2.55 min, MH+: 457.1.
Reaction SMILES: C([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Br:24])=[C:12]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:11]=1)C1C=CC=CC=1.[OH-].[Na+].CCOCC>C1COCC1.O>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]=1[Br:24])[C:9]([OH:33])=[O:8])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Yield: 80.7 %

Procedure:
To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid benzyl ester (200a) (225 g, 0.45 mol) in THF (400 mL) and H2O (500 mL) was added NaOH (89.4 g, 2.24 mol) in one portion. The mixture was refluxed for 4 hr. TLC (EtOAc/petroleum ether=1/4) showed that the reaction was complete. Et2O (100 mL) was added to the mixture and the organic layer was separated. The aqueous layer was acidified with conc. HCl, and the resulting solid was filtered and dried in vacuo to give the title compound (150 g, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 4H), 7.39(t, 4H), 7.31 (m, 4H), 5.27(s, 4H).